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Lecture Four
Topics: •Mechanisms of Antibiotic Resistance
Dr. G. Kattam Maiyoh
01/23/15 GKM/KISIIU/MBSM713 /BIOC.AMIC.AGENS.LEC04 1
MBSM 713: BIOCHEMISTRY OF ANTI MICROBIAL AGENTS
• Relative or complete lack of effect of antimicrobial against a previously susceptible microbe
Antibiotic resistance• Relative or complete lack of effect of
antibiotic against a previously susceptible bacreria
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Antimicrobial Resistance
Drugs such as tetracyclines or erythromycins are pumped back out of bacterial cells through efflux pump proteins to
keep intracellular drug concentrations below therapeutic level.
The antibiotic is destroyed by chemical modification by an enzyme that is elaborated by the resistant bacteria. This is exemplified here by the beta-lactamase secreted
into the periplasmic space to hydrolyse penicillin molecules before they reach their targets in the cytoplasmic membrane of Gram-negative bacterium.
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Resistance strategies for bacterial survival.
The aminoglycoside antibiotic kanamycin can be enzymatically modified at three sites by three kinds of enzymatic processing — N-acetylation, O-phosphorylation or O-adenylylation — to block recognition by its target on the ribosome.
The target structure in the bacterium can be reprogrammed to have a low affinity for antibiotic recognition. Here the switch from the amide linkage in the D-Ala-D-
Ala peptidoglycan termini to the ester linkage in the D-Ala-D-Lac termini is accompanied by a 1,000-fold drop in drug-binding affinity.
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Enzymatic modification
Aminoglycosides such as Kanamycin
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Target modification
Target structure in the bacterium can be reprogrammed to have a low affinity for antibiotic recognition
• Enzymatic destruction of drug
• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug (efflux)
• Resistance genes – alter
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No penetration
Summary of mechanism of resistance
1. Exposure to sub-optimal levels of
antimicrobial
2. Inappropriate antibiotic use (see next page)
3. Exposure to microbes carrying resistance
genes
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What Factors Promote Antimicrobial Resistance?
• Prescribing practices of providers e.g. use of broad spectrum antibiotics and prescribing without a laboratory request or doctor visit.
• Prescription not taken correctly• Antibiotics for viral infections – common cold• Antibiotics sold without medical supervision• Spread of resistant microbes in hospitals due to lack
of hygiene• Concerns of daycare providers (need to restrict
access).
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Examples for resistance
• Lack of quality control in manufacture or outdated antimicrobial
• Inadequate surveillance or defective susceptibility assays
• Poverty or war• Use of antibiotics in foods
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Other examples for resistance
– Growth promotion – Disease prevention– Sick animal treatment/plants – very large
amounts–Poultry–Fish farms–Fruit, potatoes, tobacco and others–Ornamental plants
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Role of antibiotics use in agriculture
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Should antibiotics for growth promotion and disease prevention be banned?
• Adverse effect on animal industry • Reduced food supply • Increased cost of production• Increased disease incidence
economic loss by farmers
• May not be totally necessary• Might only require ban of specific antimicrobial drugs
that could select for resistance to drugs in human medicine.
Consequences of Antimicrobial Resistance
• Infections resistant to available antibiotics
• Increased cost of treatment
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Current problems of Resistance/MDR bacteria
Hospital Community
Gram Negative Gram Negative
Acinetobactor sp. E. Coli
Citrobacter sp. Neisseria gonorrhoeae
Enterobacter sp. S. typhi
Klebsiella sp. S. tythimurium
P. aeruginosa
Serratia marcescens
Gram Positive Gram Positive
Enterococcus sp.: vancomycin resistant enterococci (VRE)
Enterococcus sp.: vancomycin resistant enterococci (VRE)
Coagulase negative staphylococcus Mycobacterium turberculosis
MRSA MRSA
MRSA heterogenously resistant to vancomycin
Streptococcus pneumoniae
Streptococcus pyogenes
• Methicillin-Resistant Staphylococcus aureus
• Most frequent nosocomial (hospital-acquired) pathogen
• Usually resistant to several other antibiotics
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MRSA “mer-sah”
• Speed development of new antibiotics
• Track resistance data nationwide• Restrict antimicrobial use• Direct observed dosing (TB)
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Proposals to Combat Antimicrobial Resistance
• Use more narrow spectrum antibiotics• Use antimicrobial cocktails• Tx only the sick or at risk• Producer education• Further research before imposing
bans
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Proposals to combat antimicrobial resistance
• Antimicrobial peptides
– Antibiotics from plants and animals• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)
• DNA technology
• Antisense agents– Complementary DNA or peptide nucleic acids that binds
to a pathogen's virulence gene(s) and prevents transcription
– Phage therapy - use of bacteriophages to treat pathogenic bacterial infections
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The Future of Chemotherapeutic Agents