Reframing antimicrobial resistance as a continuous spectrum of manifestations.

To fight antimicrobial resistance (AMR), we must recognize and target all its manifestations. In this review, we briefly summarize the history that led to recognition of the various manifestations of AMR in bacterial pathogens and the ways in which they interrelate. We emphasize the importance of distinguishing between AMR arising from genetic alterations versus induction of endogenous machinery in response to environmental triggers, including - paradoxically - stresses from host immunity and antimicrobial therapy. We present an integrated view of AMR by reframing it as a spectrum of phenotypes within a continuous three-dimensional space defined by the growth rate, prevalence, and kill rate of cells displaying AMR. Finally, we reflect on strategies that may help stem the emergence of AMR.

Multiform antimicrobial resistance from a metabolic mutation.

A critical challenge for microbiology and medicine is how to cure infections by bacteria that survive antibiotic treatment by persistence or tolerance. Seeking mechanisms behind such high survival, we developed a forward-genetic method for efficient isolation of high-survival mutants in any culturable bacterial species. We found that perturbation of an essential biosynthetic pathway (arginine biosynthesis) in a mycobacterium generated three distinct forms of resistance to diverse antibiotics, each mediated by induction of WhiB7: high persistence and tolerance to kanamycin, high survival upon exposure to rifampicin, and minimum inhibitory concentration-shifted resistance to clarithromycin. As little as one base change in a gene that encodes, a metabolic pathway component conferred multiple forms of resistance to multiple antibiotics with different targets. This extraordinary resilience may help explain how substerilizing exposure to one antibiotic in a regimen can induce resistance to others and invites development of drugs targeting the mediator of multiform resistance, WhiB7.

Biology of antimicrobial resistance and approaches to combat it.

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.