LYSC98 as a novel vancomycin-derived agent effective against antibiotic-resistant pathogens in tolerant state

Antibiotic resistance and tolerance pose dual challenges to clinical antibiotic therapy, with tolerance potentially accelerating resistance evolution. LYSC98, a candidate drug that has just received clinical approval in China, has been reported to have bactericidal activity against antibiotic-resistant Staphylococcus aureus. However, its mechanism and activity against antibiotic-resistant bacteria in tolerant state remains unexplored.

To evaluate the antibacterial activity of LYSC98 against antibiotic-resistant bacteria in different metabolite states, and to elucidate its mechanism of action.

MIC values of antimicrobial agents were determined using broth microdilution. Time-kill assays were used to evaluate the bactericidal effect. SEM and TEM were conducted to visualize the morphological changes. Membrane permeability was determined by propidium iodide.

LYSC98 showed potent antibacterial activity against Gram-positive pathogens, with MICs ranging from 0.06 to 2 mg/L. It demonstrated a rapid bactericidal effect against antibiotic-resistant pathogens, irrespective of their growth phase or tolerant state, and conferred an extended post-antibiotic effect. Significantly, LYSC98 displayed a low potential for resistance development. It targeted both bacterial cell wall and membrane, with in vitro membrane assays indicating selective damage to these structures and no observed harm to mammalian cells.

LYSC98's rapid bactericidal activity, selective disruption of bacteria without harming mammalian cells and low propensity for resistance development make it a novel promising candidate for combating chronic, clinically recalcitrant infections.