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2.Suppose that an organism is suddenly infected with a new pathogen and subsequently infects other members of its species. Infection with the pathogen results in ill effects on the hosts. Which of the following is FALSE:

a.The reservoir for this pathogen may have been another species, where it may have been present for a long time before making the jump.
b.The reservoir for this pathogen may have been another species, but this species had to have been a close relative of the newly infected species.
c.The new pathogen will likely have a more virulent effect on the newly infected species than would a pathogen with a longer-term presence.
d.The newly infected species may happen to have encountered other pathogens in the past that it has evolved to deal with, which confers some resistance to the new pathogen.

3.Which of the following is TRUE:

a.Most human variation exists within groups rather than between them.
b.Human races are properly classified as 'sub-species', because there are clear differences in traits that we commonly categorize as 'racial features'.
c.Eugenics had its roots in thoroughly well-grounded science, and made use of the clearest thinking about human genetic variation and the factors that went into shaping human characteristics.
d.Evolutionary medicine is an outdated and racist idea that sought to make human beings subject to the whim of prevailing social norms and ideas of "innate superiority".

4.Suppose that an organism is suddenly infected with a new pathogen and subsequently infects other members of its species. Infection with the pathogen results in ill effects on the hosts. Which of the following is FALSE:

a.The reservoir for this pathogen may have been another species, where it may have been present for a long time before making the jump.
b.The reservoir for this pathogen may have been another species, but this species had to have been a close relative of the newly infected species.
c.The new pathogen will likely have a more virulent effect on the newly infected species than would a pathogen with a longer-term presence.
d.The newly infected species may happen to have encountered other pathogens in the past that it has evolved to deal with, which confers some resistance to the new pathogen.

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Nestor RutherfordLv2
28 Sep 2019

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Related questions

CAN I GET THE ANSWER FOR THE 4TH QUIESTION PLEASE.

4- You are a wild-life biologist assigned the task of protecting bats from this disease(WNS). What one question would you like answered before you take on this challenge and why? (1 point)

White-Nose Syndrome Threatens the Survival of Hibernating Bats in North America

Map illustrating the distribution of endangered species of hibernating bats in relation to the expanding distribution of White-Nose Syndrome.

History of White-Nose Syndrome and Diseases in Hibernating Bats

During the winter of 2006–2007, an affliction of unknown origin dubbed “white-nose syndrome” (WNS) began devastating colonies of hibernating bats in a small area around Albany, New York. Colonies of hibernating bats were reduced 80–97 percent at the affected caves and mines that were surveyed. Since then, white-nose syndrome or its causative agent have been detected more than 2,000 kilometers (1,200 mi) away from the original site, and have infected bats in at least 26 U.S. states and 4 Canadian provinces. Most species of bats that hibernate in the region are now known to be affected; little brown bats (Myotis lucifugus), northern long-eared bats (M. septentrionalis), and federally listed (endangered) Indiana bats (M. sodalis) have been hit particularly hard. The sudden and widespread mortality associated with white-nose syndrome is unprecedented in hibernating bats, which differ from most other small mammals in that their survival strategy is to live life in the slow lane: their life history adaptations include high rates of survival and low fecundity, resulting in low potential for population growth. Most of the affected species are long lived (~5–15 years or more) and have only one offspring per year. Subsequently, bat numbers do not fluctuate widely over time, and populations of bats affected by white-nose syndrome will not recover quickly. Epizootic disease outbreaks have never been previously documented in hibernating bats.

An Emerging Disease of Hibernating Bats

White-nose syndrome was named for the white fungus (Pseudogynmnoascus destructans) around the muzzles, ears, and wing membranes of affected bats. Photo: Alan Hicks, New York Department of Environmental Conservation. Used with permission.

Hibernating species

Species Name

Common Name

1

Myotis auriculus

Mexican long-eared bat

2

Myotis austroriparius

Southeastern bat

3

Myotis californicus

California bat

4

Myotis ciliolabrum

Western small-footed myotis

5

Myotis evotis

Western long-eared bat

6

Myotis grisescens

Gray bat

7

Myotis keenii

Keen's bat

8

Myotis leibii

Eastern small-footed bat

9

Myotis lucifugus

Little brown bat

10

Myotis occultus

Occult bat

11

Myotis septentrionalis

Northern long-eared bat

12

Myotis sodalis

Indiana bat

13

Myotis thysanodes

Fringed bat

14

Myotis velifer

Cave bat

15

Myotis volans

Long-legged bat

16

Myotis yumanensis

Yuma bat

17

Nycticeius humeralis

Evening bat

18

Parastrellus hesperus

Canyon bat

19

Perimyotis subflavus

Tricolored bat

20

Corynorhinus townsendii

Townsend's big-eared bat

21

Corynorhinus rafinesquii

Rafinesque's big-eared bat

22

Eptesicus fuscus

Big brown bat

23

Antrozous pallidus

Pallid bat

24

Euderma maculatum

Spotted bat

25

Idionycteris phyllotis

Allen's big-eared bat

Long-distance Migrants/Non-hibernating species

Species Name

Common Name

1

Mormoops megalophylla

Ghost-faced bat

2

Choeronycteris mexicana

Mexican long-tongued bat

3

Leptonycteris nivalis

Greater long-nosed bat

4

Leptonycteris yerbabuenae

Lesser long-nosed bat

5

Macrotus californicus

California leaf-nosed bat

6

Lasionycteris noctivagans

Silver-haired bat

7

Lasiurus blossevillii

Western red bat

8

Lasiurus borealis

Eastern red bat

9

Lasiurus cinereus

Hoary bat

10

Lasiurus ega

Southern yellow bat

11

Lasiurus intermedius

Northern yellow bat

12

Lasiurus seminolus

Seminole bat

13

Lasiurus xanthinus

Western yellow bat

14

Eumops floridanus

Florida bonneted bat

15

Eumops perotis

Greater mastiff bat

16

Eumops underwoodi

Underwood's mastiff bat

17

Molossus molossus

Pallas' mastiff bat

18

Nyctinomops femorosaccus

Pocketed free-tailed bat

19

Nyctinomops macrotis

Big free-tailed bat

20

Tadarida brasiliensis

Brazilian free-tailed bat

White-nose syndrome (WNS) was named for the visible presence of a white fungus around the muzzles, ears, and wing membranes of affected bats. Based upon what is known about typical fungal pathogens of typical mammals, this fungal growth was initially thought to be a secondary infection of bats with compromised immune systems. However, bats are anything but “typical” mammals (see below). Since then, a previously unreported species of cold-loving fungus Pseudogynmnoascus [formerly Geomyces] destructans) has been identified as a consistent pathogen among affected animals and sites. This fungus, now proven to be the causal agent of WNS (Lorch et. al, 2011), thrives in the darkness, low temperatures (5–10ºC; 40–50ºF), and high levels of humidity (>90%) characteristic of bat hibernacula. Unlike typical fungi, Pseudogynmnoascus destructans cannot grow above 20°C (68ºF), and therefore appears to be exquisitely adapted to persist in caves and mines and to colonize the skin of hibernating bats. A consistent pattern of fungal skin penetration has been observed in more than 90 percent of bats from the WNS-affected region that were submitted for disease investigation.

White-nose syndrome was first documented in a cave that is visited by tens of thousands of tourists each year, and the disease has since spread outward from that site. The focal area of origin and subsequent distribution of affected sites, as well as experimental evidence (Werneke et. al, 2013), indicate that P. destructans could be an exotic species with the capacity to spread rapidly among populations of hibernating bats. Researchers in Europe have long noticed similar fungal growth on the faces, ears, and wings of hibernating bats in Europe, but observed no associated mortality. Work is currently underway to assess whether there is any connection between fungi seen on bats in North America and Europe. Recent efforts by researchers in Europe have revealed that P. destructans occurs on hibernating bats in several countries of that continent. An alternative hypothesis for the origin of white-nose syndrome is that this fungus was already present in North America, yet recently mutated to become an emerging disease.

What Makes Bats Susceptible to White-Nose Syndrome?

Pathologic findings thus far indicate that bats affected by white-nose syndrome are infected by P. destructans, and many appear to prematurely run out of the stored body fat that they rely on for winter survival. Species of bats occurring at the higher latitudes of the world rely on insects for food, which disappear from those temperate zones during winter. Most species of temperate zone bats survive the winter by building up fat reserves during autumn and then going to cold places to hibernate and wait out the winter insect shortage. During hibernation, a bat slows down its metabolism so that its body temperature remains just a few degrees above air temperature. This strategy allows a bat to consume very little fat over winter. Bats could easily last several months in this deep state of torpor, but they need to warm their bodies up a few times each winter and arouse from hibernation so that they can drink, urinate, mate, relocate, and probably induce their immune systems to catch up. These natural arousals from hibernation consume a lot of energy, and about 90 percent of a hibernating bat’s winter fat is burned to fuel natural arousals. If anything increases the frequency or duration of such arousals during winter, the energy balance of a hibernating bat can quickly tip toward starvation. Chronic disturbance of hibernating bats is known to cause abnormal arousal patterns, and can result in high rates of winter mortality. For example, certain inappropriate research methods (e.g., poorly applied wing bands and frequent winter visitations) directed toward hibernating bats in the 1950s and 1960s caused chronic disturbance that led to high mortality and population declines in several U.S. bat species (Ellison 2008). Unlike typical microbial pathogens that cause collapse of internal organ systems, the skin infection caused by P. destructans may act as a chronic disturbance during hibernation, and fungal-associated aberrant behaviors likely cause bats to consume critical body reserves too quickly during winter. In addition to disrupting hibernation cycles and prematurely expending energy reserves, it is likely that affected bats suffer other serious physiological problems (e.g., dehydration) associated with the fungus infecting the proportionally huge skin surfaces of their wings during hibernation.

The newly identified cold-loving fungus is now known to be the primary causative agent of white-nose syndrome. Available evidence suggests the fungus establishes itself in the skin tissues of bats when their body temperatures are lowered during torpor (2–10ºC; 35–50ºF). Although life-threatening cutaneous fungal infections of this sort are rare in warm-blooded birds and mammals, they occur more frequently in “cold-blooded” animals (e.g., chytridiomycosis in amphibians, and crayfish plague). The cold-loving fungus seems to be infecting bats when they reduce their body temperatures during hibernation to levels characteristic of “cold-blooded” animals. Fungal infiltration of the wing membranes of bats may be particularly problematic. Wing membranes represent about 85 percent of a bat’s total surface area and play a critical role in balancing complex physiological processes. Healthy wing membranes are vital to bats, as they help regulate body temperature, blood pressure, water balance, and gas exchange—not to mention the ability to fly and to feed. Although white-nose syndrome was named after the obvious sign of white noses on affected bats, bat wings may indeed be the most vulnerable point of infection.

Because the newly identified fungus represents a potential biological invasion or emerging disease, with severe implications for hibernating bats in North America, it is important to focus on the history of its geographic distribution in the context of the distributions of affected species and those of federal concern that are potentially in harm’s way.

Threat Posed by White-Nose Syndrome to Bat Diversity and Abundance in North America

Forty-five species of bats occur in the United States and Canada, and bats represent more than 10 percent of mammalian species diversity in the region. The map at right shows bat species richness in the continental United States and Canada. Warmer colors represent higher species richness, cooler colors represent fewer species.

More than half of the species of insectivorous bats that occur in the U.S. rely on hibernation as a primary strategy for surviving the winter when insect prey is not available. The table at right lists all 45 species of bats known to occur in the continental United States and Canada. Species in the upper list are those that in most areas rely on hibernation to survive the winter. Species in the lower list are those that generally do not rely on hibernation as a winter survival strategy. Those highlighted in bold text are species currently known to be affected by white-nose syndrome.

The emergence and spread of a pathogenic fungus that infects hibernating bats has the potential to undermine the basic survival strategy of more than half the bat species in the U.S. and all species of bats that occur in the higher latitudes of North America. With the exception of 4 species of migratory tree bats, the other 18 bat species that occur above 40ºN in North America (roughly a line running from the top of California across Nebraska to Virginia) hibernate to survive the winter.

The shaded red areas on the map below represent the overlapping distributions of 19 species of bats occurring in the U.S. that do not rely on hibernation as a strategy for surviving the winter. The blue shaded areas of the map below represent the overlapping distributions of 25 species of bats occurring in the U.S. that rely on hibernation to survive the winter. The distributions of four species of migratory tree bats are not shown.

Overlapping Species of Bats

Figure 1. Maps illustrating the overlapping ranges of non-hibernating (left) and hibernating (right) species of U.S. bats.

Among the 25 species of bats that hibernate across North America, 4 species and subspecies are federally listed as endangered and an additional 13 are federal species of concern (former Category 2 candidates for listing under the U.S. Endangered Species Act). All four endangered species and subspecies of hibernating bats in the U.S., which rely on undisturbed caves or mines for successful hibernation, are at risk from white-nose syndrome. Three of these species are currently within the affected area, and the remaining subspecies may be affected in the next few years, if not sooner.

The maps included in the slideshow above show the distribution of endangered species of hibernating bats (shaded areas) in relation to the expanding distribution of the fungus (Pseudogynmnoascus destructans) and the disease white-nose syndrome (yellow counties). Endangered species include Ozark big-eared bats (Corynorhinus townsendii ingens), Virginia big-eared bats (C. t. virginianus), Indiana bats (M. sodalis), and gray bats (M. grisescens). For an updated map of sites affected by WNS see https://www.whitenosesyndrome.org/.

Although the true potential for this fungus to spread is unknown, the possibility of it undermining the ubiquitous survival strategy of bats at higher latitudes has enormous implications. We are just beginning to appreciate the roles that bats play in North American ecosystems, and it is clear that threats like white-nose syndrome have the potential to influence ecosystem function in ways that we currently do not understand.

Since white-nose syndrome emerged during the winter of 2006–2007, a diverse group of scientists, resource managers, and conservation groups have worked diligently to establish its cause. Efforts are now being directed toward developing solutions to the WNS crisis and minimizing its impact on populations of hibernating bats in North America.

Video Clip of Hibernating Bats and Small Tussle

A winter scene from a Virginia cave showing an interaction between two little brown bats (Myotis lucifugus) that have aroused from hibernation. This video was recorded in darkness by FORT scientists and their research partners using a custom-built surveillance system that is the first of its kind. These new observations are shedding new light on bat hibernation behaviors and how white-nose syndrome affects wintering bats.

USGS scientists at the National Wildlife Health Center and Fort Collins Science Center are supporting the research needs of the U.S. Fish and Wildlife Service and other federal and state agencies as they respond to the developing situation.

Map data compiled by Cal Butchkoski, Pennsylvania Game Commission.

© Photos by Alan Hicks, New York Department of Environmental Conservation

_________________________________________________________________________________________________________________________________________

It was the winter of 2006-2007. In what may be the worst calamity to hit bat populations in the United States, a mysterious affliction began to decimate bat colonies in upper New York State. On average, 90 percent of the hibernating bats in four caves and mines in New York succumbed that winter. The affliction, now known as White-Nose Syndrome (WNS), is estimated to have killed over six million bats in the eastern United States and has spread as far west as Missouri since that time. Read the following article about WNS White-Nose Syndrome Threatens the Survival of Hibernating Bats in North America and answer the questions that follow.

1- What is the causative agent of WNS and to what phylum does it belong? (1 point)

Pseudogymnoascus destructans, which is formerly known as Geomyces destructans, is the causative agent of WNS. P destructans belong to Ascomycota phylum from the Fungi kingdom.

2- What is unique about this causative agent that makes it particularly well adapted to its lifestyle (adapted to persist in caves and mines and to colonize the skin of hibernating bats)? (1 point)

Thrives in the darkness, low temperatures (5–10ºC; 40–50ºF), and high levels of humidity (>90%) characteristic of bat hibernacula. Unlike typical fungi, Pseudogynmnoascus destructans cannot grow above 20°C (68ºF)(cold living fungus).

3- What makes a hibernating bat a particularly easy target for the pathogen? (1 point)

Available evidence suggests the fungus establishes itself in the skin tissues of bats when their body temperatures are lowered during torpor (2–10ºC; 35–50ºF). Although life-threatening cutaneous fungal infections of this sort are rare in warm-blooded birds and mammals, they occur more frequently in “cold-blooded” animals (e.g., chytridiomycosis in amphibians, and crayfish plague). The cold-loving fungus seems to be infecting bats when they reduce their body temperatures during hibernation to levels characteristic of “cold-blooded” animals. Fungal infiltration of the wing membranes of bats may be particularly problematic.

4- You are a wild-life biologist assigned the task of protecting bats from this disease. What one question would you like answered before you take on this challenge and why? (1 point)

???????????????????????????

Question: From the Article Below, write a review of the current status of development of antibiotics." I do not have the figures!"

Article: Antibiotic discovery in the twenty-first century: current trends and future perspectives

New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment.

Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for

new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent

with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However,

many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially

effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities

have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use.

Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected

examples, we offer our view on the future of antibiotic discovery.

The Journal of Antibiotics advance online publication, 16 June 2010; doi:10.1038/ja.2010.62

Keywords: antibiotics; natural products; pipeline

Medical progress in the prevention and treatment of many diseases,

which have resulted in significantly increasing life expectancy, may be

put at risk without the introduction into clinical practice of new

antibiotics effective against multidrug-resistant (MDR) pathogens.

Although most stakeholders agree that new antibiotics could tackle

this unmet medical need, opinions vary on how new antibiotics could

be discovered and brought into the market in a cost-effective manner.

1–3 Two considerations would probably meet with unanimous

consensus: the golden era of antibiotic discovery is gone and it will not

be repeated; and genomics, combinatorial chemistry and highthroughput

screening do not represent the magic bullet to fill the

pipeline with new developmental drug candidates. In this respect, it is

important to underline the contribution that natural products,

especially those of microbial origin, can provide to antibiotic discovery,

as advocated by Demain4,5 on several occasions. The decreasing

number of drugs approved for clinical use, year after year, suggests

that the ‘ailing pharmaceutical industry’ is not yet following the

‘prescription’ of Demain,6 as spelled out in 2002.

The purpose of this review is to highlight some of today’s features of

antibiotic discovery in the context of the current medical needs and

the existing pipeline of antibacterial agents in clinical development.

Our main focus will be on chemical classes that, if developed into

drugs, would be new to the clinic. However, these classes would not

necessarily be new to science. For example, a ‘look-back’ strategy was

applied to antibiotics discovered during the golden era, which were

then reexamined using contemporary tools in the light of current

medical needs.7 Although some important breakthroughs have also

been made in identifying new promising drug candidates from

synthetic origin, for reason of space, and in the spirit of the important

contributions to the field by Demain, we would limit ourselves

to antibiotics of microbial origin and their derivatives reported

since 2005.

CURRENT ANTIBIOTIC PIPELINE

Infections due to methicillin-resistant Staphylococcus aureus (MRSA),

vancomycin-resistant Enterococcus faecium (VRE) and fluoroquinolone-

resistant Pseudomonas aeruginosa are rapidly increasing in US

hospitals, and even more frightening is the recent occurrence of

panantibiotic-resistant infections, involving Acinetobacter species,

MDR P. aeruginosa and carbapenem-resistant Klebsiella species.8,9

Although antibiotic resistance continues to grow in hospitals and in

the community, involving both Gram-positive and Gram-negative

pathogens, the number of newly approved agents has been decreasing,

with only six new antibiotics approved since 2003.

In the late 90s, following the global concern regarding the rapid

increase in MRSA, many companies redirected their attention to target

Gram-positive pathogens, particularly MRSA, VRE and penicillinresistant

Streptococcus pneumoniae, as evidenced by the commercial

and clinical success of linezolid and daptomycin, the only antibiotics

belonging to new classes introduced in clinical practice since the early

1960s. However, most antibiotics currently under development for

Gram-positive infections are improved derivatives of existing drugs

(see Table 1). As vancomycin has been increasingly used for the

treatment of a wide range of infections, second-generation glycopep-

tides with improved profile over vancomycin were developed. Among

them, telavancin, a once-a-day derivative of vancomycin, was

approved by the US Food and Drug Administration (FDA) in 2009.

Oritavancin, derived from the vancomycin-related glycopeptide chloroeremomycin,

is highly active against VRE strains and shows a long

plasma half-life. However, in 2008, the FDA did not authorize its

commercialization. The long-acting glycopeptide dalbavancin, a derivative

of the teicoplanin-related glycopeptide A40926, was also not

approved by FDA, because of insufficient clinical evidence of efficacy.

If approved, dalbavancin would be the first antibiotic to be administered

once weekly.10

Resistance to methicillin in S. aureus is mediated by the production

of a penicillin-binding protein with reduced affinity for b-lactams. The

most recent cephalosporins, ceftobiprole and ceftaroline (Table 1),

have been specifically designed to enhance activity against MRSA and,

thanks to their oral availability, are particularly attractive for the

community setting. Ceftobiprole is quickly bactericidal against a wide

range of Gram-positive pathogens, including MRSA and VRE and has

been approved in Canada and Switzerland.11 However, early in 2010,

the FDA did not grant market authorization to ceftobiprole, and later

the European authority issued a negative opinion on this compound.

Ceftaroline, which is active against most Gram-positive pathogens

with the exclusion of enterococci, has completed phase III studies and

may be submitted for FDA approval.12 Both cephalosporins, however,

lose potency against MRSA compared with methicillin-susceptible

S. aureus strains. The injectable carbapenem PZ-601 has shown potent

activity against drug-resistant Gram-positive pathogens, including

MRSA, and is currently undergoing phase II studies.13

After the success of linezolid, many new oxazolidinones are being

developed for Gram-positive infections. Radezolid14 and torezolid15

are currently in phase II trials, whereas RWJ-416457 has completed the

phase I trial. Despite the fact that the use of fluoroquinolones has been

associated with increased incidence of MRSA,16 several new members

of this class are under development: delafloxacin, nemonoxacin,

zabofloxacin and WCK-771 (Table 1) are the most advanced.

The extensive use of fluoroquinolones and other wide-spectrum

antibiotics such as cephalosporins, by affecting the normal gut flora,

has led to the rapid diffusion of Clostridium difficile-associated

diarrhea, particularly in elderly and immunocompromised patients.

Difimicin, currently in phase III, and ramoplanin, with phase II

completed, are microbial products under development for prevention

and treatment of C. difficile-associated diarrhea, acting locally by

decolonizing the gut (Table 1).

Other compounds which have completed phase I clinical trials

include the oral and injectable pleuromutilin BC-3205,17 the FabI

inhibitor AFN-1252 targeting staphylococcal infections18 and the

lipopeptide friulimicin (Table 1).19

The scenario is even more disappointing for compounds targeting

Gram-negative pathogens, in which old drugs have been revamped for

new uses, and none of them has reached phase III yet (Table 1).

Ceftazidime is a marketed cephalosporin being developed in combination

with NXL104, a representative of a new class of b-lactamase

inhibitors,20 which renders cephalosporin effective against most

b-lactamase-producing enterobacteria. If approved, this combination

would be the first alternative to piperacillin/tazobactam. NXL104 is

also under investigation in combination with ceftaroline.21 CXA-101 is

a ceftazidime-like compound with improved stability against the

AmpC b-lactamase, but it shows no improvements against MDR

P. aeruginosa,22 unless administered in combination with tazobactam.

The new aminoglycoside ACHN-490, effective against pathogens

resistant to this class, has recently completed phase I.23 The new

monobactam BAL-30072, stable against metalloenzymes, is ready to

start clinical development against difficult-to-treat Gram negatives,

including Pseudomonas and Acinetobacter.24

The increasing spread of MDR Gram-negative pathogens, particularly

P. aeruginosa, Acinetobacter spp. and some Enterobacteriaceae has

renewed the interest toward narrow-spectrum compounds, to avoid

other clinical conditions associated with the use of broad-spectrum

antibiotics. However, because of a long history of success in the

empirical treatment of infections, many hospitals lack rapid and

effective tools for identifying etiological agents. This limitation poses

significant hurdles for the clinical development of narrow-spectrum

compounds.

APPROACHES LEADING TO NEW ANTIBIOTIC CLASSES

It is generally agreed that the best way to overcome the decreasing

efficacy of existing antibacterial agents is to introduce into practice

compounds belonging to classes that are new to the clinic. Microbial

sources can provide a rich reservoir of such compounds, and the

different approaches used usually aim at discovering either a novel

class or an improved variant of a poorly explored class. However,

this must be carried out in a high background of many known

compounds, some of which are encountered in random screening

programs at a relatively high frequency. Thus, the discovery of an

antibacterial agent belonging to a new chemical class or an improved

variant of an existing class is a rare event, and the approaches

described below reflect strategies designed and implemented to

capture this rare event. Appropriate strategies include retrieving

microbial strains from underexplored environments, screening new

microbial taxa, mining microbial genomes and using innovative

assays. These strategies have led to some novel chemical classes, as

illustrated in Figure 1.

As an example of the first strategy, investigation of deep-sea

sediment samples led to the discovery of abyssomicins (Figure 1),

which are polycyclic antibiotics from the new marine actinomycete

taxon Verrucosispora.25 The compounds were discovered using a simple

agar diffusion assay, which involved pursuing antibiotics the action of

which could be reverted upon addition of p-aminobenzoic acid.

Abyssomicins represent a new chemical class, and preliminary studies

indicate that they act as substrate mimics of chorismate. Interestingly,

only abyssomicin C and its atrop stereoisomer show antibiotic activity

against Gram-positive bacteria, including MDR S. aureus.26

An additional example of a new chemical class discovered by

screening new taxa is represented by thuggacins (Figure 1), which

are thiazole-containing macrolides produced by the myxobacteria

Sorangium cellulosum and Chondromyces crocatus.27 These compounds

show activity against Mycobacterium tuberculosis and their target

appears to be the electron transport chain.

Another successful approach has been exploring microbial genomes

for the presence of secondary metabolite pathways. As the corresponding

genes are organized in clusters and bioinformatic tools allow

a reasonable prediction of the pathway product, this bioactivityindependent

approach can directly target structural novelty. On a

pioneering work of this type, scientists at Ecopia Biosciences (now

Thallion Pharmaceuticals, Montreal, QC, Canada) identified ECO-

02301, a linear polyene from Streptomyces aizunensis with antifungal

activity28 and ECO-0501, a glycosidic polyketide from Amycolatopsis

orientalis with activity against Gram-positive pathogens, including

MDR isolates (Figure 1).29 In a similar approach, a novel cyclic

lipopeptide, designated orfamide (Figure 1), was identified from the

Pseudomonas fluorescens genome.30 In this case, the bioinformatic

prediction that the peptide contained four leucine residues suggested

feeding with 15N-Leu, which facilitated compound purification and

characterization. Orfamide shows a moderate antifungal activity

against amphotericin-resistant strains of Candida albicans and may

prove beneficial in agriculture and crop protection.

Another important strategy for discovering new classes of antibiotics

has been the implementation of increased-sensitivity assays in

screening programs. One such approach relied on the antisense

technology. When the level of a desired bacterial target is depleted

by overexpression of the cognate antisense mRNA, the strain becomes

hypersensitive to compounds acting on that target. By using a target

against which few compounds are known to act, the increased

sensitivity of the assay should allow the identification of compounds

routinely missed with growth inhibition assays on the wild-type

strain.31 One assay involved the FabH/FabF enzyme, required for

fatty acid biosynthesis in bacteria. Antimicrobial activities were

detected by agar diffusion in a two-plate assay, in which one plate

was inoculated with S. aureus carrying the antisense construct and the

other plate with an S. aureus control. Different inhibition halos in the

two plates indicated an increased sensitivity of the ‘antisense strain.’

After screening 4250 000 microbial product extracts, the assay led to

the identification of a new chemical class that includes platensimycin

(Figure 1), produced by Streptomyces platensis, and related compounds.

Platensimycin shows antibacterial activity against Grampositive

pathogens, including MDR strains, and was also effective in

an experimental model of infection.32

In another increased-sensitivity assay, a high-throughput screening

program was implemented to identify inhibitors of a cell-free translational

system affecting steps other than elongation. The assay made

use of a model ‘universal’ mRNA that could be translated with similar

efficiency by cell-free extracts from bacterial, yeast or mammalian cells.

The rationale behind the approach was to use a sensitive assay and to

discard frequently encountered compounds using a polyU-based assay.

This program led to the identification of GE81112 (Figure 1), a novel

tetrapeptide produced by a Streptomyces sp., which targets specifically

the 30S ribosomal subunit by interfering with fMet-tRNA binding to

the P-site.33 The compound was highly effective against a few Grampositive

and Gram-negative strains, if grown in minimal or chemically

defined medium, suggesting active uptake by the cells.34

The above examples illustrate how different approaches can lead to

novel antibiotic classes. Usually, when unexploited microbial diversity

is accessed, there is no need for specific, high-sensitivity assays.

Whichever the approach chosen, there is no guarantee of success.

The reader is referred to a recent review for suggestions on how to

increase the probabilities of success.35

IMPROVED VARIANTS FROM MICROBIAL SOURCES

New variants of known classes can be found by screening microbial

strains, by varying cultivation procedures or by manipulating the

biosynthetic pathway. There is an increasing amount of literature

related to pathway manipulation and this trend is likely to continue as

methodological advancements result in increased success rates. In

some cases, the desired variant might not be a more active compound,

but a molecule carrying functional groups suitable for further chemical

modifications. As the antibiotics in clinical use belong to a few

classes, which have been extensively explored by screening and

chemical modification, there is probably little space for finding

improved variants within those classes. We provide selected examples

of microbial strains producing improved variants of chemical classes

not yet in clinical use.

Lantibiotics, which are ribosomally synthesized peptides that

undergo posttranslational modifications to yield the active structures

containing the typical thioether-linked (methyl)lanthionines, are produced

mostly from strains belonging to the Firmicutes and, to a lesser

extent, to the Actinobacteria. Their antimicrobial activity is limited to

Gram-positive bacteria. The prototype molecule is nisin, discovered in

the 1920s and used as a food preservative for440 years.36 Lantibiotics

with antibacterial activity are divided into two classes according to

their biogenesis: lanthionine formation in class I compounds requires

two separate enzymes, a dehydratase and a cyclase, whereas a single

enzyme carries both activities for class II lantibiotics. Until recently,

the occurrence of class I compounds was limited to the Firmicutes (see

below). Although compounds from both classes exert their antimicrobial

activity by binding to Lipid II, they do so by binding to

different portions of this key peptidoglycan intermediate.

As lantibiotics bind Lipid II at a site different from that affected by

vancomycin and related glycopeptides, they are active against MDR

Gram-positive pathogens and have attracted attention as potential

drug candidates. The compound NVB302, a derivative of deoxyactagardine

B (Figure 2a) produced by a strain of Actinoplanes liguriae, is

currently a developmental candidate for the treatment of C. difficileassociated

diarrhea.37 Independently, a screening program, designed to

detect cell-wall-inhibiting compounds turned out to be very effective

in identifying lantibiotics from actinomycetes.38 It consisted of identifying

extracts active against S. aureus but inactive against isogenic

L-forms, discarding extracts the activity of which was abolished by

b-lactamases or by excess N-caproyl-D-alanyl-D-alanine. Among the

new lantibiotics identified, the most active compound was NAI-107

(Figure 2a), produced by Microbispora sp.39 This compound represents

the first example of a class I lantibiotic produced by actinomycetes. It

is currently a developmental candidate for the treatment of nosocomial

infections by Gram-positive pathogens.40 The same screening

program led to the identification of additional class I lantibiotics from

actinomycetes. Among them, the compound 97518 (Figure 2a),

structurally related to NAI-107,41 afforded improved derivatives by

chemical modification.42 Another interesting advancement in the

lantibiotic field has been the discovery of two-component lantibiotics

produced by members of the class Bacilli. The best characterized

compound is haloduracin43,44 (Figure 2a), whereas lichenicidin has

been proposed from genomic studies but has not yet confirmed by

structural elucidation.45 Although their antimicrobial activities have

not been described in detail, recent work suggests similar activities for

haloduracin and nisin.44

Thiazolylpeptides are highly modified, ribosomally synthesized

peptides that inhibit bacterial protein synthesis by affecting either

one of two targets: elongation factor Tu, as for GE2270 and related

compounds; or the loops defined by 23S rRNA and the L11 protein,

exemplified by thiostrepton. Most thiazolylpeptides show potent

activity against Gram-positive pathogens, yet their poor solubility

has limited clinical progress, and only a derivative of GE2270 has

entered clinical trials for the topical treatment of acne.46 Novel

members of this class have been described (Figure 2b): thiomuracins47

belong to the subgroup targeting EF-Tu, with an antibacterial profile

similar to GE2270; thiazomycin48 and philipimycin,49 which target the

50S subunit, show high activity against Gram-positive strains, and a

similar profile to thiostrepton.

For ribosomally synthesized peptides, such as lantibiotics and

thiopeptides, new representatives can be generated by site-directed

mutagenesis of the corresponding structural genes. Libraries of new

molecules have been obtained, many of which, as in the examples of

actagardine50 and thiocillin,51 retained antibiotic activities comparable

with those of the parent molecule.

CHEMICAL DERIVATIVES

Many papers have been published in the past 5 years reporting

chemical programs aimed at overcoming the prevailing resistance

mechanisms and/or to improve the drug profile of known microbial

products. Novel approaches included the use of new tools, such as

click chemistry and total synthesis. For the classical approach of semisynthesis,

we will limit the examples to selected compounds not yet in

clinical use.

Click chemistry is a new synthetic approach that can accelerate drug

discovery by using a few practical and reliable reactions. A ‘click’

reaction must be of wide scope, giving consistently high yields with

various starting materials; it must be easy to perform, insensitive to

oxygen or water and use only readily available reagents; finally,

reaction work-up and product isolation must be simple, without

chromatographic purification.52 As an example, this approach was

used to produce new lipophilic teicoplanin and ristocetin aglycons

with improved activity against Gram-positive bacteria, including

VRE.53 For aminoglycosides, which usually require multiple protection–

deprotection steps to selectively manipulate the desired amino

and hydroxyl groups, click chemistry allowed the transformation

of neomycin B into several novel building blocks that were used for

the specific modification of the ring systems, thus generating new

neomycin analogs the biological activity of which is currently under

investigation.54

For some low-molecular-weight compounds, total synthesis has

become available and will be useful to design preliminary SAR for new

classes of antibiotics (such as platensimycin) or to access new

derivatives for already known classes (such as tetracyclines). Indeed,

the novel scaffold and intriguing biological property of platensimycin

captured the interest of several research groups, which reported

different elegant total syntheses.55 In addition, medicinal chemistry

studies have been conducted, and the design, synthesis and biological

evaluation of several platensimycin analogs incorporating varying

degrees of molecular complexity have been reported.56–58 Preliminary

data indicate that certain modifications of the intricate cage region can

be made without detrimental effects on potency, whereas even small

modifications of the benzoic acid region result in a drastic loss of

activity (Figure 1). Another remarkable chemical improvement in the

synthesis of natural product analogs was a short and enantioselective

synthetic route to a diverse range of 6-deoxytetracycline antibiotics

(Figure 3a). This new approach targeted not a single compound but a

group of structures with the D ring as a site of structural variability.

A late-stage, diastereoselective C-ring construction was used to couple

structurally varied D-ring precursors with an AB precursor containing

much of the essential functionality for binding to the bacterial

ribosome. Results of antibacterial assays and preliminary data

obtained from a murine septicemia model show that many of the

novel tetracyclines synthesized have potent antibiotic activities. This

synthetic platform gives access to a broad range of tetracyclines that

would be inaccessible by semi-synthesis and provides a powerful

engine for the discovery of new tetracyclines.59,60

Even on larger molecules, semi-synthetic and synthetic chemistry

has been successfully applied to study and optimize lead compounds.

The lipoglycodepsipeptide ramoplanin (Figure 3b) is 2–10 times more

active than vancomycin against Gram-positive bacteria and maintains

full activity against VRE and all MRSA strains. However, its systemic

use has been prevented by its low tolerability at the injection site,

apparently related to the length of the fatty acid side chain.

To overcome this problem, the fatty acid side chain was selectively

removed and replaced with different carboxylic acids. Many derivatives

showed an antimicrobial activity similar to that of the precursor,

and a significantly improved local tolerability.61 The recently

described, fully synthetic lactam analog of ramoplanin showed the

same biological activity as the natural product. Moreover, a set of

alanine analogs, obtained by total synthesis, has provided insights into

the importance of individual amino-acid residues on ramoplanin

activity. The MICs of each alanine-containing analog parallels its

ability to bind Lipid II. Apart from positions 5, 6 and 9, which can

tolerate alanine substitutions, MICs increased 415-fold upon alanine

replacement, with dramatic effects observed for positions 4, 8, 10 and

12. The new data thus confirm the importance of the ornithine

residues at positions 4 and 10, with the latter directly involved in

target binding, most likely by ion pairing with the diphosphate of

Lipid II.62,63

The mannopeptimycins, which were originally isolated in the late

1950s from Streptomyces hygroscopicus, have been recently revived

because of their promising activity against clinically important Grampositive

pathogens, including S. pneumoniae, MRSA and VRE. They

also bind to Lipid II, but in a manner different from ramoplanin,

mersacidin and vancomycin. Multiple approaches have been used to

optimize the mannopeptimycin activity profile, including selective

chemical derivatization, precursor-directed biosynthesis and pathway

engineering. The SAR data have shown that substitution of a hydrophobic

ester group on the N-linked mannose or serine moieties

suppressed antibacterial activity, whereas hydrophobic acylation on

either of the two O-mannoses, particularly the terminal mannose,

significantly enhanced activity. AC98-6446 (Figure 3b) represents an

optimized lead obtained by adamantyl ketalization of a cyclohexyl

analog prepared by cyclohexylalanine-directed biosynthesis. AC98-

6446 showed superior antimicrobial potency and properties, both

in vitro and in vivo.7,64

Laspartomycin is active against VRE and MRSA strains. Recently,

enzymatic cleavage of its lipophilic moiety allowed the synthesis of

various acylated derivatives (Figure 3b), even if none was more potent

than the parent antibiotic.65 The cyclic heptapeptide GE23077 is a

potent and selective inhibitor of bacterial RNA polymerase

that, probably because of its hydrophilicity, is unable to cross

bacterial membranes. New derivatives obtained by modifying different

moieties were reported. Although many of them retained activity

on the enzyme, none showed a significant antibacterial activity

apart from marginal inhibition of Moraxella catarrhalis growth

(Figure 3b).66

FUTURE PERSPECTIVES

This brief and nonexhaustive excursus on the present and future

pipeline of antibacterial agents for treating human diseases provides

opportunities for additional considerations. The first is that, of the

antibiotics under clinical development (Table 1), 67% are natural

products themselves, or natural product-derived compounds, a percentage

perfectly in line with that found with exisiting drugs.67

The second consideration is that the major players in antibacterial

development are small companies, which are not deterred by the small

market size for these drugs. However, it should be noted that a

significant number of the compounds listed in Table 1 were not

discovered by small companies, but actually represent projects abandoned

by large pharmaceuticals companies. Thus, it remains to be

seen whether small biotechs will dedicate sufficient resources and be

successful in discovering and developing novel antibacterial agents.

In this relatively grim scenario, microbial products continue to

provide new chemical classes or unexpectedly active variants of

chemical classes already known to science. New technologies can

now provide access to unexplored microbial diversity or to hypersensitive

assays to detect bioactive compounds. Furthermore, the information

derived from rapidly accessing the genome of many microbial

strains can provide new routes to natural product discovery, as well as

making more effective traditional, bioassay-based screening efforts.

In our opinion, no single technology will represent the magic bullet

for antibiotic discovery, but only the painstaking integration of a

multidiscplinary team with profound knowledge of microbiology,

chemistry and bioinformatics will ultimately lead to new antibacterial

agents of medical relevance and commercial success.

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