Antibiotic resistance mechanisms

Enzymatic drug interactions

Enzyme modify active nucleus of the drug (cleavage of molecules or addition of a chemical group ( eg., B-lactams, aminoglycosides, chloramphenicols)

Drug inactivation enzymes are usually related with mobile genetic elements β-lactamase and aminoglycoside enzymes are most prevalent.

Β-lactamases hydrolyze the beta lactam ring, which are no longer able to bind active serine site of peptidoglycan layer (4 class A-D)

Aminoglycosidase modifying enzymes catalyze transfer of acetyl group that drug poorly binds to ribosome.

Chloramphenicol is inactivated by chloramphenicol acetyltransferase

Target modification

(penicillin, glycopeptides, MLS, quinolones)

  1. Mutation in penicillin binding proteins on bacterial cell membrane
  2. Replace alanine with lactate in peptidoglycan by changing peptide component from d-alanine-d-alanine to d-alanine-d-lactate (Resistance to vancomycin)
  3. Change peptide component from d-alanine-d-alanine to d-alanine-d-lactate
  4. Mutation in catalase-peroxide (tuberculosis)
  5. Mutation in DNA gyrase (Quinolone resistance – chromosomal mutation)
  6. Mutation in RNA polymerase, Chromosomal mutation in gene for B subunit of bacterial RNA polymerase (Resistance to rifampin)

This mechanism particularly important for penicillins, glycopeptides and MLS in gram-positive bacteria.

MRSA (methicillin resistant Staph aureus (+); mecA synthesis new PBP (penicillin binding proteins)

Glycopeptides resistant Enterococcus (Vancomycin resistant Enterococcus) is in this class (vanA and vanB peptidoglycan ending changes).

Efflux pumps

(tetracycline, chloramphenicols, nalidixic acid, novobiocin)

  • The most relevant bacterial efflux system families involved in antibiotic resistance are: ABC, MFS, MATE, RND and SMR (Li et al., 2015).

Group in sequence similarity:

  1. Major facilitator (MF) family (EmrAB and MdfA)
  2. RND family (AcrAB, AcrD, AcrEF, MdtABC and MdsAB)
  3. Multidrug and toxic compound extrusion (MATE) family (MdtK)
  4. ATP-binding cassette (ABC) family

Group in specificity:

  • Specific drug resistance efflux pump (tetracycline in gram neg and MLS or phenicols)
  • Multi drug resistance efflux pump

OR Group in energy source:

  • ATP binding cassette (ABC) transporters; utilize ATP for energy source; MLS
  • Secondary drug transporters; utilize proton and sodium ions MDR resistance.

OR Group in size:

  • MFS (Major facilitator super-family)
  • SMR( Small multi-drug resistance)
  • RND (resistance nodulation cell division)

efflux.jpg

ghg

ref: https://doi.org/10.1093/jac/dkq160 , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC99009/

Reduction of permeability

(ompC, ompF mutations)

Mutations leading loss, reduced size, decrease expression of porins can cause reduce drug uptake. OmpF and OmpC are most common genes can mutate and alter porins. The combined presence of blaCMY-2 and a lack of OmpF and OmpC have been previously associated with imipenem resistance in Ecoli (carbapenem).

Β-lactams and fluoroquinolones in gram negative bacteria is most common.

  • Compared with gram-positive species, gram-negative bacteria are intrinsically less permeable to many antibiotics as their outer membrane forms a permeability barrier
  • One mechanism that results in reduced drug permeability in bacteria is the cell wall’s lipo polysaccharide (LPS), which consists of lipid A, a core consisting of polysaccharide and O-antigen . Bacteria that harbor LPS moieties show resistance to erythromycin, roxithromycin, clarithromycin and azithromycin in gram-negative bacteria such as strains of Pseudomonas aeruginosa and Salmonella enterica, all of which are serious pathogens, especially in immune-compromised patients.

Mutation in porin proteins commonly cause penicillin and aminoglycoside resistance.

ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696358/ , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764994/

Target protection

Mostly seen in  tetracycline (TetM and TetO), fluoroquinolones (Qnr) and fusidic acid (FusB and FusC).

Alternative pathways 

Chromosome mutation increase number of PABA receptors (folic acid synthesis) for Sulfonamides.