NhaA: A promising adjuvant target for colistin against resistant Escherichia coli

Int J Biol Macromol. 2024 Apr 23:131833. doi: 10.1016/j.ijbiomac.2024.131833. Online ahead of print.ABSTRACTThe emergence and widespread of multidrug-resistant Gram-negative bacteria have posed a severe threat to human health and environmental safety, escalating into a global medical crisis. Utilization of antibiotic adjuvants is a rapid approach to combat bacterial resistance effectively since the development of new antimicrobial agents is a formidable challenge. NhaA, driven by proton motive force, is a crucial secondary transporter on the cytoplasmic membrane of Escherichia coli. We found that 2-Aminoperimidine (2-AP), which is a specific inhibitor of NhaA, could enhance the activity of colistin against sensitive E. coli and reverse the resistance in mcr-1 positive E. coli. Mechanistic studies indicated that 2-AP induced dysfunction in cytoplasmic membrane through the suppression of NhaA, leading to metabolic inhibition and ultimately enhancing the sensitivity of E. coli to colistin. Moreover, 2-AP restored the efficacy of colistin against resistant E. coli in two animal infection models. Our findings reveal the potential of NhaA as a novel target for colistin adjuvants, providing new possibilities for the clinical application of colistin.PMID:38663703 | DOI:10.1016/j.ijbiomac.2024.131833
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Source Type: research