Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance

IMPORTANCE OF THE FIELD: The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one molecule. The possible benefits include: i) activity against drug-resistant bacteria, ii) expanded spectrum of activity and iii) reduced potential for generating bacterial resistance. AREAS COVERED IN THIS REVIEW: In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compounds with emphases on their potential to reduce resistance development. WHAT THE READER WILL GAIN: Recently developed synergistic and antagonistic antibacterial drug-drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Additionally, we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances. TAKE HOME MESSAGE: The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compounds are entering clinical trials. However, the key challenge in this area should be a broader experimental demonstration of whether the "synergistic effect" or the "antagonistic effect" of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug.