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

ABSTRACT 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% (MIC 50 ) and 90% (MIC 90 ) 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 log 2 dilution of MIC values, and >3-log 10 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.