Lecture 04.2014

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

01/23/15GKM/KISIIU/MBSM713

/BIOC.AMIC.AGENS.LEC042

Antimicrobial Resistance

Figure 20.2001/23/15GKM/KISIIU/MBSM713


Antibiotic 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.



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.





A. Efflux pumps



B. Enzymatic destruction of drug



Enzymatic modification

Aminoglycosides such as Kanamycin



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



No penetration

Summary of mechanism of resistance



Antibiotic Selection for Resistant Bacteria

1. Exposure to sub-optimal levels of

antimicrobial

2. Inappropriate antibiotic use (see next page)

3. Exposure to microbes carrying resistance

genes



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).



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



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



Role of antibiotics use in agriculture



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





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



Multi-Drug Resistant TB

• Methicillin-Resistant Staphylococcus aureus

• Most frequent nosocomial (hospital-acquired) pathogen

• Usually resistant to several other antibiotics



MRSA “mer-sah”

• Speed development of new antibiotics

• Track resistance data nationwide• Restrict antimicrobial use• Direct observed dosing (TB)



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



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



The Future of Chemotherapeutic Agents

Thank you for your attention



Healthcare

Lecture 04.2014