Targets for Combating the Evolution of Acquired Antibiotic Resistance.
Bottom Line: This recognition underscores the importance of understanding how such genetic changes can arise.We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets.We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.
Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal.
Mentions: RecA isa highly conserved∼38 kDa protein that plays a critical role in homologous recombinationand also acts to stimulate LexA self-cleavage.43 Structurally, monomeric RecA consists of three domainswith a central core RecA fold that is flanked by smaller regulatorydomains.44 These monomers can form largenucleoprotein filaments on ssDNA (Figure 4A),which can extend across thousands of base pairs via cooperative oligomerizationmediated by the core RecA fold.45 FilamentousRecA has a deep helical groove that envelopes, stretches, and unwindsthe bound DNA, preparing it for homology searching and subsequentDNA strand exchange. The core RecA fold binds ATP at the monomer–monomerinterface (Figure 4A).44 While only binding of ATP is required for filament formation andsimple DNA strand exchange reactions, RecA also catalyzes ATP hydrolysis,which is important for filament depolymerization as well as some specifictypes of recombination activities.43