LTX-315 is a novel broad-spectrum antimicrobial peptide against clinical multidrug-resistant bacteria

Introduction: Infections stemming from multidrug-resistant bacteria present a substantial threat to public health today. Discovering or synthesizing novel compounds is crucial to alleviate this pressing situation. Objective: The main purpose of this study is to verify the antibacterial activity of LTX-315 and explore its primary action mode. Methods: Through antibacterial phenotype assay screening, we obtained a potent compound named LTX-315 from diverse drug libraries, 10,926 compounds in total. Then, the bactericidal effect and its action mode were explored through biochemical and chemistry methods such as a time-killing curve, scanning electronic microscopy, isothermal titration calorimetry analysis, and nuclear magnetic resonance. Finally, the efficacy in vivo of LTX-315 against drug-resistant bacteria was proved through a mice infection model. Results: In this study, LTX-315, an oncolytic peptide, was discovered to effectively eliminate gram-positive and gram-negative pathogens, even for those multidrug-resistant strains. Through strong electrostatic interactions, LTX-315 can bind to the membrane component phosphatidylglycerol (PG) with extremely high affinity (nanomolar level). Strikingly, in contrast to the typical electrostatic interactions of antibacterial peptides, the indole group of LTX-315, situated near the alkyl chain, exhibits significantly enhanced recognition and interaction with PG due to the hydrophobic effect of the alkyl chain. Furthermore, it exerts various impacts on cell membranes, including damaging integrity, increasing permeability, and decreasing membrane fluidity. Additionally, microscopy revealed significant cell disintegration. The influence, in turn, disrupts several physiological activities inside cells, such as increasing the reactive oxygen species level, ultimately leading to cell death. Finally, the efficacy of LTX-315 in vivo against multidrug-resistant and hypervirulent Klebsiella pneumoniae was demonstrated. Conclusion: The unique mechanism of LTX-315 involves high-affinity binding to PG and subsequent membrane disruption, providing a novel approach against multidrug-resistant bacteria compared to conventional antibiotics. As a potential candidate, it shows promise in effectively treating bacterial infections, particularly those caused by drug-resistant bacteria, thereby addressing the escalating challenge of antibiotic resistance worldwide. © 2024 Published by Elsevier B.V. on behalf of Cairo University.