BMS2052 Lecture Notes - Lecture 20: Topoisomerase, Dna Replication, Antiviral Drug
30 May 2018
School
Department
Course
Professor
Week 8. Antimicrobials and resistance
• Antimicrobials:
o Selective inhibitors of microbial growth
(unlike disinfectants and antiseptics which kills everything)
o Therapeutic class of drugs with the largest impact on life expectancy at birth
o Arguably the first custom-made pharmaceuticals
o “tarted the agi ullet oept for oder seletie drugs
-> can specifically kill one type of cell without killing a human cell
• 1910 = Salvarsan
• 1935 = Prontosil
• 1942 = Penicillin
• 1946 = Streptomycin
• General properties of antimicrobials:
o Exploit structural and biochemical differences between microbial and mammalian cells
o Narrow spectrum: may only be able to kill a few related species/strains
o Broad spectrum: kill multiple different species and usually it means both gram positive
and negative
o Whether narrow or broad spectrum is usually a matter of permeability – envelopes are
different
o Natural:
Produced by all microorganisms
Obtained commercially by fermentation of producer organisms
o Semisynthetic:
Introduce new minor modifications
Chemically modified natural products
o Synthetic :
Made in lab from beginning, not derived from a natural source
Purely synthetic starting point
• Microbiological effect:
o Static agents:
Number stays the same
Stops the increase in viable cell numbers
Cure by allowing host defence mechanisms to cope with infection (as long as
iroorgais does’t reprodue
o Cidal agents:
Number decreases
Reduce the number of viable microbial cells
Triggers stress response – cell commits suicide
o May be cytocidal for one organism but cytostatic for another
-microbial factors play a role
find more resources at oneclass.com
find more resources at oneclass.com
• Antimicrobial targets:
o Macromolecules (mostly enzymes) unique to the microbial cell or highly divergent from
the human homologues - to allow us to kill with selectivity
o Metabolic processes which can be by-passed in humans but not in the pathogen
eg. folate incorporation from dietary sources
-> we can take folate from diet but most bacteria do not have transporters for folate
-> inhibit folate synthesis or recycling -> we can selectively kill the bacteria without
killing the host -> can give host supplements
o Few different targets used by marketed compounds – natural antibiotics have very few
differet targets do’t ko h
• Klebsiella pneumoniae:
o Gram negative
o Non-motile
o Capsulated rod
o Host to mobile genetic elements – can acquire resistance very easily
o Usually part of normal flora that sometimes enter oropharynx and causes respiratory
problems – if immunocompromised = infections
• Nosocomial bacterial pneumonia case study:
o Klebsiella pneumoniae is the causative agent (elderly, alcoholic male)
o Poor outcome regardless of treatment
- HAP (hospital acquired)
- VAP (ventilator associated)
o First line of treatment (assumed S. pneumoniae):
B-lactam (eg. high dose ampicillin)
Will be active if it can enter outer membrane – new ones can do this
o Assumed to produce extended spectrum beta lactamases (ESBL) - enzymes that confer
resistance to most beta-lactam antibiotics
o B-lactams resistant to most B-lactamases: carbapenum (resistant to most but not all)
and aminoglycoside
o No improvement -> susceptibility testing indicates presence of carbapenemase
o Genetic analysis shows integrin encoding resistance to antifolates, all B-lactams,
aminoglycosides, fluoroquinolones and tetracycline
o Last resort:
Colistin plus rifamoicin – normally poorly active against enterobacteria
Colistin is toxic
o If pathogen has acquired resistance to colistin (mcr-1 element) then here is nothing left
to try -> patient has 50% chance of dying
• B-lactam antibiotics:
o B lactam ring structurally resembles D-Ala-D-Ala (found in PG) from the NAM-NAG
pentapeptide (natural substrate of enzyme that makes PG)
o targets PG so we can take grams of it and it will not harm us (but will affect normal flora)
find more resources at oneclass.com
find more resources at oneclass.com
o binds to cross linking enzymes (BPBs - what gives PG its shape and strength) and forms a
long lived acyl enzyme
o Under-crosslinked PG provides less support against turgor pressure
-less support against osmotic pressure and bacterium will lyse (due to inhibitor)
-when bacteria grows, PG needs to be cleaved and insert new material
o Imbalance between PG synthesis and degradation at growth points, deregulates
autolytic activities – bacteria will self-destruct
o Ineffective against Archaea, mycoplasmas and intracellular bacteria (impermeable)
-do’t hae PG
o Different classes and arranged complexity
o Usually first safe choice
• B-lactamase mediated resistance:
o Enzyme that sits in periplasm of gram negative (usually not present in gram positive –
will diffuse away because they lack the outermembrane)
o Resistance to B-lactams due to:
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Obtained commercially by fermentation of producer organisms: semisynthetic: Chemically modified natural products: synthetic : Made in lab from beginning, not derived from a natural source. Purely synthetic starting point: microbiological effect, static agents: Cure by allowing host defence mechanisms to cope with infection (as long as. Stops the increase in viable cell numbers (cid:373)i(cid:272)roorga(cid:374)is(cid:373) does(cid:374)"t reprodu(cid:272)e(cid:895: cidal agents: Reduce the number of viable microbial cells. Triggers stress response cell commits suicide: may be cytocidal for one organism but cytostatic for another. > we can take folate from diet but most bacteria do not have transporters for folate. Vap (ventilator associated: first line of treatment (assumed s. pneumoniae): Colistin plus rifamoicin normally poorly active against enterobacteria. Less support against osmotic pressure and bacterium will lyse (due to inhibitor) When bacteria grows, pg needs to be cleaved and insert new material. Imbalance between pg synthesis and degradation at growth points, deregulates autolytic activities bacteria will self-destruct.
