When did resistance to naturally occurring antibiotics develop?
Thousands of years ago
The rapid spread of resistance to some antibiotics is attributed to horizontal gene transfer and selective pressure due to the presence of antibiotics in the environment. Explain how the presence of antibiotics and the resulting selective pressures lead to resistance.
The antibiotic works as a selective mechanism by repressing growth and cell division of those susceptible to the antibiotic and favoring growth of resistant ones.
What are 3 possible ways resistance may have originally developed?
- Resistance genes may have originated in microorganisms that produce antibiotics
- From common ‘housekeeping’ genes
- By Spontaneous Mutation (Note: occurs at a very low rate of 10^-12 to 10^-7)
Decreased cell permeability is often a defense mechanism to antibiotics. From Gram-, Gram+, and acid-fast bacteria, rank from most resistant to least resistant to antibiotics on the basis of their membrane permeability. Why?
Acid-fast (mycolic acid) > Gram- > Gram+
- Acid fast bacteria have the waxy mycolic acid layer that acts as a very efficient permeability barrier. This mycolic acid layer has porins but they are more restrictive than those in Gram- bacteria.
- Gram- bacteria have two membranes, meking them a decent permeability barrier. Large porins in outer membrane greatly increase the permeability of the outer layer however.
- Gram+ bacteria only have a cytoplasmic membrane and a cell wall. Cell wall = very permeable.
A mutation in what protein might provide a bacterial cell with resistance to penicillin?
A mutated penicillin binding protein such as transpeptidase.
Why might mutated peptidoglycan structure give a bacterial cell resistance to Vancomycin antibody?
Vancomycin has to recognize peptidoglycan and bind to it in order to stop it from crossing the membrane, therefore, if the composition changed, vancomycin may no longer be able to recognize, and therefore bind to, peptidoglycan.
How might ribosome protection help guard a cell against tetracycline?
The ribosome protector subunit could bind to the ribosome tetracycline binding domain, therefore tetracycline wouldn’t be able to recognize and bind the ribosomal subunit and stopping translation.
Mutated DNA gyrase may provide resistance to what two related antibiotics?
Quinolones and fluoroquinolones, which both inhibit DNA replication by binding to gyrase and deactivating it.
How does B-lactamase/penicillinase (lamB gene) provide bacteria resistance to penicillin?
A bacteria might aquire the lamB gene via horizontal gene transfer allowing it to produce penicillinase/B-lactamase enzyme.
- This enzyme cleaves the B-lactam bond (remember: the bond essential essential for function to all antibiotics in the penicillin family).
- The cleavage changes the conformation of penicillin, so that it is no longer a structural analog to D-alanyl-D-alanine and transpeptidase (PBP) will no longer bind to it.
Bacteria may acquire the gene for chloramphenicol-transacetylase enzyme, which modifies an antibiotic to render it inactive. What is the antibiotic? What change is made?
Chloramphenicol-transacetylase converts two hydroxyl groups on the binding domain of chloramphenicol antibiotic.
-This change inactivates chloramphenicol, making it unable to bind the 50s subunit of prokaryote ribosomes and inhibit translation.
Cells that are most sensitive to tetracycline actively transport the tetracycline into the cytoplasm. Describe two methods by which gene acquisition may incur resistance to tetracycline (includes 1 we’ve seen already).
- Acquisition of gene product that binds to 30s ribosomal subunit (Ribosome protection - seen previously)
- Acquisition of a gene product that pumps the antibiotic out of the cell (EFFLUX)
What is the primary mechanism by which resistance to antibiotics is transferred via horizontal gene transfer?
Transfer of CONJUGATIVE PLASMIDS and CONJUGATIVE TRANSPOSONS.
- Transduction is a more limited method.
- Resistance NOT due to spontaneous mutation.
What is MRSA? Why is it so dangerous?
MRSA stands for Methicillin-resistant Staphylococcus aureus.
- MRSA is a “superbug” resistant to many forms of antibiotics.
- Staphylococcus aureus, which may cause abscesses and toxic shock, was first effectively killed via penicillin.
- However, widespread use of penicillin resulted in high incidence of B-lactamase producing strains in hospitals. So treatment was switched to Methicillin.
- Methicillin resistant strains rapidly appear. Creating MRSA, which is resistant to both penicillin AND methicillin.
- Vancomycin is the last line of defense to treat MRSA and other resistant strains of Staphylococcus aureus.