Biology of antimicrobial resistance and approaches to combat it

Abstract

Insufficient development of new antibiotics and the rising resistance of bacteria to those that we have are putting the world at risk of losing the most widely curative class of medicines currently available. Preventing deaths from antimicrobial resistance (AMR) will require exploiting emerging knowledge not only about genetic AMR conferred by horizontal gene transfer or de novo mutations but also about phenotypic AMR, which lacks a stably heritable basis. This Review summarizes recent advances and continuing limitations in our understanding of AMR and suggests approaches for combating its clinical consequences, including identification of previously unexploited bacterial targets, new antimicrobial compounds, and improved combination drug regimens.

Fig. 1.. Genetic and phenotypic AMR.

The schematic shows genetic AMR (left) compared to an example of phenotypic AMR (right). Left: In genetic AMR, a bacterium with a mutation that gives it the potential to resist an antibiotic (red cell, first row) survives exposure to that drug (second row) and continues to proliferate, whereas the susceptible majority (blue cells, first row) die (pale blue cells, second row). The resistant bacterium (red) continues to proliferate and pass its mutation on to its progeny even when the antibiotic is removed (third row). Upon a second exposure to antibiotic (fourth row), all the bacterial cells survive and continue to grow during exposure. Right: In contrast, in phenotypic AMR, a bacterial cell is genetically identical to its siblings but happens to be in a metabolic state that is conducive to surviving the first exposure to antibiotic (gray cell, first row). When removed from the antibiotic, this bacterium gives rise to a population resembling that from which it arose so that the second exposure to antibiotic kills the same proportion of the bacterial population as before (fourth row). ABX, antibiotic [adapted from (107)].

Fig. 2.. Three characteristics distinguish four types of AMR in vitro.

The four types of AMR observed in vitro are as follows: heteroresistance, persistence, resistance, and tolerance. These four types of AMR can be distinguished by a combination of three characteristics: prevalence, growth rate, and kill rate. Different values of these three characteristics enable diverse AMR phenotypes. In clinical settings, different AMR phenotypes may pertain to the disease-causing bacterial pathogen inside or outside host cells, in different anatomical sites, and at different times during the course of the infection and its treatment.