LYSG101: a potent chimeric lysin with therapeutic potential for combating Staphylococcus aureus infections

Lysins are peptidoglycan hydrolases with great promise as novel and highly differentiated biotherapeutic agents. Here, we characterize LYSG101, a chimeric lysin active against all Staphylococcus species, including Staphylococcus aureus. LYSG101 exhibits potent activity against a range of clinical isolates, including methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci (CoNS). Minimum inhibitory concentrations that inhibited 50% (MIC₅₀) and 90% (MIC₉₀) of S. aureus strains tested were 1 and 2 µg/mL, respectively, in cation-adjusted Mueller-Hinton broth (CAMHB) and 0.0625 and 0.125 µg/mL, respectively, in CAMHB + 25% horse serum, with no resistant outliers. LYSG101 is bactericidal, based on minimum bactericidal concentration (MBC) values within one log₂ dilution of MIC values, and >3-log₁₀ reduction within 15 min of exposure to lysin in time-kill assays. Serial passage resistance assays demonstrated no development of resistance to LYSG101 following 100 daily passages, whereas mupirocin resistance increased up to 500-fold over the same period. LYSG101 effectively disrupted S. aureus and CoNS biofilms. In vivo, LYSG101 significantly improved survival in murine models of intraperitoneal and intravenous S. aureus infection at 0.25 mg/kg (P < 0.01 for both), and resulted in a significant reduction in lung CFU (P < 0.0001) in a neutropenic lung infection model. These findings support the potential of LYSG101 as a new and effective therapeutic agent for staphylococcal infections.