Mechanisms of Antibiotic Resistance

In the United States more than 2 million people are infected with antibiotic-resistant bacteria annually, with 23,000 deaths as a direct result. In addition to increased resistance to existing agents, there is a lack of new antibiotics in development. The word antibiotic has become synonymous with ‘antibacterial drug’: therefore, in this article the term antibiotic has been used throughout.

Bacteria can be intrinsically resistant to certain antibiotics but can also acquire resistance to antibiotics via mutations in chromosomal genes and by horizontal gene transfer. The intrinsic resistance of a bacterial species to a particular antibiotic is the ability to resist the action of that antibiotic as a result of inherent structural or functional characteristics. The simplest example of intrinsic resistance in an individual species results from the absence of a susceptible target of a specific antibiotic; for example, the biocide triclosan has broad efficacy against Gram-positive bacteria and many Gram-negative bacteria, but it is unable to inhibit growth of members of the Gram-negative genus Pseudomonas. Although this was initially thought to be due to active efflux, it has more recently been shown that it is instead due to the carriage of an insensitive allele of fabI that encodes an additional enoyl-ACP reductase enzyme — the target for triclosan in sensitive species. A second example relates to the lipopeptide daptomycin (first approved for clinical use in 2003), which is active against Gram-positive bacteria but is not effective against Gram-negative bacteria. This is due to an intrinsic difference in the composition of the cytoplasmic membrane; Gram-negative bacteria have a lower proportion of anionic phospholipids in the cytoplasmic membrane than do Gram-positive bacteria, which reduces the efficiency of the Ca2+-mediated insertion of daptomycin into the cytoplasmic membrane that is required for its antibacterial activity. The intrinsic resistance of some Gram-negative bacteria to many compounds is due to an inability of these agents to cross the outer membrane: for example, the glycopeptide antibiotic vancomycin inhibits peptidoglycan crosslinking by binding to target d-Ala-d-Ala peptides but is only normally effective in Gram-positive bacteria as, in Gram-negative organisms, it cannot cross the outer membrane and access these peptides in the periplasm…

To learn more about antibiotic resistance, take a look at the following paper in Nature.

Nature Reviews Microbiology13,42–51(2015)doi:10.1038/nrmicro3380