The state of the art in dual-acting hybrid antibiotics to combat bacterial resistance

The efficacy of current treatments for bacterial infections is under threat due to the continuing rise in the prevalence of antimicrobial resistance (AMR). Resistance can arise due to a wide variety of changes in the bacterial cell that prevent the antibiotic from acting on its target. This can be through changes to the target itself or changes that limit access to the target. Strategies to overcome resistance therefore either seek to reestablish access to the target or to engage a different target for which resistance is yet to arise. This has been done successfully in the clinic through co-dosing of more than one molecule, but a long-held aim has been to achieve efficacy in a single 'hybrid' molecule. The authors review the progress since 2016 of hybrid antibiotics in clinical trials, cover some advances in preclinical research into dual-acting hybrids, and examine alternative approaches to using bi-functional hybrid molecules to tackle AMR. Many contributory factors, both scientific and economic, have limited the success of dual-acting hybrids where both partners are antibiotics. The success of cefiderocol highlights the potential of linking molecules that target bacteria directly and non-antibiotics. These strategies offer some exciting possibilities.