A Novel Chimeric Lysin Shows Superiority to Mupirocin for Skin Decolonization of Methicillin-Resistant and -Sensitive Staphylococcus aureus Strains

Abstract

Staphylococcus aureus is a major human pathogen responsible for a number of serious and sometimes fatal infections. One of its reservoirs on the human body is the skin, which is known to be a source of invasive infection. The potential for an engineered staphylococcus-specific phage lysin (ClyS) to be used for topical decolonization is presented. We formulated ClyS into an ointment and applied it to a mouse model of skin colonization/infection with S. aureus. Unlike the standard topical antibacterial agent mupirocin, ClyS eradicated a significantly greater number of methicillin-susceptible S. aureus (MSSA) and -resistant S. aureus (MRSA) bacteria: a 3-log reduction with ClyS as opposed to a 2-log reduction with mupirocin in our model. The use of ClyS also demonstrated a decreased potential for the development of resistance by MRSA and MSSA organisms compared to that from the use of mupirocin in vitro. Because antibodies may affect enzyme function, we tested antibodies developed after repeated ClyS exposure for their effect on ClyS killing ability. Our results showed no inhibition of ClyS activity at various antibody titers. These data demonstrate the potential of developing ClyS as a novel class of topical antimicrobial agents specific to staphylococcus.

Antimicrobial bacteriophage-derived proteins and therapeutic applications

“…88 Yet both approaches easily promote bacterial resistance to antibiotics. 65,77,78,88 This is not surprising since phage have likely evolved their viral proteins that are essential for survival over millions of years. For endolysins, this requires targeting sites within the peptidoglycan matrix that are essential for bacterial viability that cannot be modified without some consequence.…”

“…Researchers have failed to identify resistant mutants after repeated exposure to sub-lethal concentrations of endolysin in vitro. 65,77,78,83 Even mutagenesis of endolysin-sensitive strains could not promote resistant derivatives. 88 Yet both approaches easily promote bacterial resistance to antibiotics.…”

“…65,77,78,88,97 There are no described resistance mechanisms or reports of bacteria losing sensitivity to 'lysis from without' by endolysins. Researchers have failed to identify resistant mutants after repeated exposure to sub-lethal concentrations of endolysin in vitro.…”

“…77 As a topical ointment, ClyS was more effective than mupirocin, the antibiotic commonly prescribed for nasal S. aureus infection treatment. 78 Endolysins can reduce S. aureus burden in the bloodstream and prevent septic death in rodents. Treatment within 30 minutes after a systemic challenge of MRSA with a single 0.05 mg (»2 mg/kg) intraperitoneal injection of endolysin MV-L was able to improve mouse survival by 100%.…”

Physiology and Pathology of Multidrug-Resistant Bacteria: Phage-Related Therapy

“…The modular structure of the endolysins targeting Gram-positive bacteria is appropriate to evolve into efficacious drugs. A chimeric lysozyme ClyS, developed by fusing Ply Twort endolysin EAD and phi13 phage NM3CBD, reduced MRSA from nasal passage and showed better effect than mupirocin treatment [104,105]. Furthermore, combination therapy of endolysin and antibiotics can be more effective in relieving MRSA infection [104].…”