Lack of Spontaneous and Adaptive Resistance Development in Staphylococcus aureus Against the Antimicrobial Peptide LTX-109.

Abstract

Nasal carriage of Staphylococcus aureus and its antibiotic-resistant derivative, methicillin-resistant S. aureus (MRSA), is a risk factor for nosocomial S. aureus infections. Mupirocin is a topical antibiotic and a key in the decolonization of both methicillin-susceptible S. aureus (MSSA) and MRSA carriage in patients and health care personnel. Recent observations have shown a global increase in the prevalence of mupirocin-resistant MSSA and MRSA, reducing the efficacy of mupirocin in decolonization regimens. LTX-109 is a peptidomimetic synthetic compound that has shown broad-spectrum bactericidal antimicrobial activity in vitro and in animal experiments. However, the development of resistance against LTX-109 in clinical isolates of MRSA and MSSA has not been systematically examined.

Background/objectives: Here, we assess the development of spontaneous and adaptive resistance against LTX-109 in genomically diverse MRSA (n = 3) and MSSA (n = 4) strains.

Methods: Adaptive and mutational resistance were examined by serial passaging strains over 60 cycles in a range of LTX-109 and mupirocin concentrations. Spontaneous resistance was examined in high-inoculum agar plates with 2-8 times the concentration above MIC.

Results: Throughout serial passage, LTX-109 MICs varied less than 4-fold compared to the initial MIC of 4-8 mg/L, while mupirocin MICs increased in all susceptible strains (n = 5) from 0.25 mg/L to 16-512 mg/L. The spontaneous resistance assay demonstrated no resistance development at 4-8× MIC LTX-109 and an inoculum effect at 2× MIC.

Conclusions: Our results demonstrate the novelty of LTX-109 as an antimicrobial agent with no detectable in vitro resistance development in selected clinical strains of MRSA and MSSA.