Genetic Basis of Resistance in Microorganisms

Genetic Basis of Resistance

• Chromosome-mediated resistance: mutation in gene coding for target of the drug or transport system in membrane controlling drug entry into cells
• Plasmid-mediated resistance: occurs in many species, especially gram-negative rods; plasmids mediate resistance to multiple drugs; high rate of transfer from one cell to another, usually by conjugation
• R factors: resistance plasmids with two sets of genes; resistant transfer genes (encode sex pilus and proteins for plasmid DNA transfer during conjugation) and drug resistance genes (encode proteins for drug resistance)
• R factors can replicate independently of bacterial chromosome; can be transferred to cells of the same or different species
• Transposon-mediated resistance: transposon-resistance genes transferred within or between large pieces of chromosomal DNA or plasmids

Mechanisms of Resistance

• Enzymatic inhibition: bacteria produce enzymes that inactivate the drug (e.g., β-lactamases)
• Alteration of target sites: altered ribosomal target sites, altered cell wall precursor targets, altered target enzymes
• Alteration of bacterial membranes: outer membrane permeability, inner membrane permeability

Penicillins and Cephalosporins

• Mechanism of action: inhibition of cell wall synthesis
• Mechanism of resistance: cleavage by β-lactamases (penicillinases and cephalosporinases); clavulanic acid and sulbactam are penicillin analogues that bind strongly to β-lactamases and inactivate them

Level of Resistance

• High-level resistance: resistance that cannot be overcome by increasing the dose of the antibiotic; often results from enzyme-mediated resistance (e.g., β-lactamases)
• Low-level resistance: resistance that can be overcome by increasing the dose of the antibiotic; often results from mutations in the gene encoding a drug target

Molecular Genetics of Antibiotic Resistance

• Genetic basis of drug resistance: mediated by genetic change in bacteria; three types: chromosome-mediated, plasmid-mediated, and transposon-mediated resistance

Other Antibiotics

• Carbapenems: resistance caused by carbapenemases that degrade the β-lactam ring; produced by many enteric gram-negative rods (e.g., Klebsiella, Escherichia, Pseudomonas)
• Tetracyclines: resistance due to failure of the drug to reach an inhibitory concentration inside the bacteria; caused by plasmid-encoded processes that reduce uptake or enhance transport out of the cell
• Chloramphenicol: resistance due to plasmid-encoded acetyltransferase that acetylates the drug
• Sulfonamides: resistance mediated by plasmid-encoded transport system that actively exports the drug out of the cell and chromosomal mutation in the gene coding for the target enzyme dihydropteroate synthetase
• Trimethoprim and Quinolones: resistance due to mutations in the chromosomal gene encoding dihydrofolate reductase and chromosomal mutations that modify DNA gyrase, respectively

Use of Antibiotic Combinations

• To treat serious infections before the identity of the organism is known
• To achieve an inhibitory effect against certain organisms
• To prevent the emergence of resistant organisms

Overuse and Misuse of Antibiotics

• Overuse in humans: using multiple antibiotics when one would be sufficient, prescribing unnecessarily long courses of antibiotic therapy, using antibiotics in self-limited infections for which they are not needed, and overusing antibiotics for prophylaxis before and after surgery
• Overuse in animals: using antibiotics in animal feed to prevent infections and promote growth; selects for resistant organisms in animals and may contribute to the pool of resistant organisms in humans

This quiz covers the genetic basis of resistance in microorganisms, including chromosome-mediated resistance, plasmid-mediated resistance, and R factors. It explores how microorganisms develop resistance to multiple drugs through gene mutations and plasmid transfer.