11 Mechanisms of drug resistance

Question 1

Bacterial Resistance Mechanisms

Answer 1

• Microorganisms have various mechanisms that counter anti-microbial agents
• 4 main mechanisms/strategies exist:
  
  • Inhibition of drug uptake into bacterial cell
    
    • modify porin channel, making it smaller keeping drugs like:
      
      • Aminoglycosides (kept out by gram negatives)
      • Quinolones (kept out by gram negatives)
      • Beta-lactams (now cant get to PBPs)
      • Pseudomonas aeruginosa against imipenem
      • Vancomycin intermediate S.aureus (VISA)* strains with thickened cell wall against vancomycin- trapping it
      • ​Vancomycin-resistant Staph aureus (VRSA) * changes D-ala-D-ala to D- ala-D-lactate in pentapeptide chain via VanA gene transfered by vancomycin resistant enterococcus
      • Resistance of Enterococci to vancomycin*
    • Expulsion of drug from bacterial cell via efflux pumps, pumping out:
      
      • macrolides (staphylocci)
      • lincosamides
      • steptogramins (staphylocci)
      • tetracyclines (e. coli and other enterobacteriaceae)
      • fluoroquinolones- the drugs ending in floxicin (Staph aureus & Streptococcus)
    • Inactivation of drug via modification or degradation
      
      • Against beta-lactam drugs (via beta-lactamase enzyme*)
        
        • penicillins and cephalosporins
        • extended-spectrum beta-lactamases
      • chloramphenicol (via acetyltransferase enzyme produced by many enterobacteriaceae)
      • aminoglycosides (by prosphorylases, adenylases and acetylases via gram negative and gram positive bacteria)
      • inactivated penicilloic acid cannot bind to PBPs (penicillin binding proteins
    • Modifying drug target within bacterial cell
      
      • Alteration in PBPs leading to reduced affinity of beta lactum drugs*
        
        • Methicillin-resistant Staph aureus * - encodes mecA gene
          
          • _​and oxacillin*_
        • Streptococcus pneumoniae**, Group A streptococci resistance to penicillin**
        • Neisseria gonorrhoeae
        • Listeria monocytogenes

Question 2

intrinsically resistant to Penicillins

Answer 2

intrinsically resistant to Penicillins

Mycoplasma

Question 3

Plasmid-mediated Drug resistance**

Answer 3

Plasmid-mediated Drug resistance**

• The genes that determine this resistance are located on plasmids
• Often these genes code for enzymes that modify the drug
• R factors are conjugative plasmids carrying genes for Drug resistance
• How do plasmids carrying resistance to multiple drugs arise ?
  
  • Transposons/gene cassettes

note:

An R plasmid consists of a resistance transfer factor (RTF), which enables conjugation, and one or more r-determinants: genes conferring resistance to antibiotics.

Question 4

Transposon * (drug resistance)

Answer 4

Transposon * (drug resistance)

• Insertion sequences + one other gene (at least)
• Include some genes for drug resistance
• Play an important role in building multiple drug resistance plasmids *
• They may also move to the chromosome (not frequently)

Question 5

Staphylococcus aureus resistance

Answer 5

Staphylococcus aureus resistance to Penicillin

• Mechanism of resistance to penicillin – production of **Penicillinase enzyme* **(a beta-lactamase enzyme)
• The gene for Beta-lactamase is part of a Transposable element located on a large plasmid, often with other antimicrobial resistance genes (eg. Gentamicin and erythromycin)
• Spread of penicillin resistance primarily occurs by spread of resistant strains
• At present – more than 90% Staph isolates resistant*

Question 6

mechanism resistance against Chloramphenicol

Answer 6

mechanism resistance against Chloramphenicol

Production of acetyltransferase

• Inactivation of drug by acetylation