Targets for Combating the Evolution of Acquired Antibiotic Resistance

Abstract

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.

Improving target amino acid selectivity in a permissive aminoacyl tRNA synthetase through counter-selection

“…1, 2 In a second example, the bacterial repressor-protease LexA uses a complex sequence of RecA-induced structural change, self-proteolysis, and dissociation of subunits to sense DNA damage and activate genes that ultimately lead to antibiotic resistance. 3, 4 Finally, the conformational flexibility of the neuronal protein α-synuclein (αS) is a liability, as it leads αS to misfold and form amyloid fibrils that contribute to the pathogenesis of Parkinson’s disease. 5, 6 Fluorescence spectroscopy is a powerful tool for studying such processes, as it allows one to observe protein motions in real time under physiological conditions, including measurements in live cells.…”

SOS Response and Staphylococcus aureus: Implications for Drug Development

“…These approaches involve inhibiting the SOS-mediated mutagenesis induced by drugs and thus improving their long-term viability. In these cases, LexA and RecA represent potential targets [53,54]. In fact, the number of SOS inhibitors is still limited and most of the studies use E. coli as model [55,56].…”

Endless resistance. Endless antibiotics?

“…186–188 This evolution is multi-dimensional. Its directions include not just the mechanism(s) of the resistance against a particular antibacterial, but the spectrum of thought ranging from reflection on the ecological purpose of the antibiotics, to the criteria necessary to attain the multi-agent synergy against infectious disease that the future may demand.…”