Lysostaphin is a naturally occurring enzyme produced by the bacterium Staphylococcus simulans. This enzyme exhibits potent antimicrobial properties, specifically targeting certain bacteria.
Mechanism of Action
Lysostaphin exerts its antimicrobial effect by targeting the bacterial cell wall, a rigid outer layer that maintains the structural integrity of bacteria. The cell wall of Staphylococcus aureus, for example, is primarily composed of peptidoglycan, a complex mesh-like polymer. This peptidoglycan layer derives much of its strength from specific connections called pentaglycine cross-bridges.
Lysostaphin functions as an endopeptidase, a type of enzyme that breaks specific peptide bonds within proteins. Specifically, it is a glycylglycine endopeptidase and a zinc-dependent metalloendopeptidase. It precisely cleaves the pentaglycine cross-bridges found within the Staphylococcus cell wall, often between the third and fourth glycine residues.
This action can be thought of as molecular scissors cutting the structural supports of a building. By severing these cross-links, lysostaphin weakens the cell wall, leading to its rupture and subsequent death.
The effectiveness of lysostaphin is enhanced by a C-terminal cell wall-targeting domain (CWT), which ensures the enzyme is directed specifically to the peptidoglycan layer. This domain selectively binds to the pentaglycine bridges, bringing the catalytic part of the enzyme into close proximity with its target. The high proportion of pentaglycine in S. aureus cell walls makes them particularly susceptible to this enzymatic breakdown.
Specificity Against Staphylococcus Aureus
Lysostaphin demonstrates a high degree of selectivity, primarily targeting Staphylococcus aureus. This specificity stems from the unique composition of S. aureus cell walls, which contain a high abundance of the pentaglycine cross-bridges that lysostaphin is designed to cleave. The enzyme is inactive against bacteria from other genera.
This targeted approach offers a distinct advantage over broad-spectrum antibiotics, which eliminate a wide range of bacteria, including beneficial ones that reside in the body. By focusing on S. aureus, lysostaphin can potentially reduce the disruption to the body’s natural microbial balance.
The enzyme’s effectiveness extends to Methicillin-resistant Staphylococcus aureus (MRSA), often referred to as a “superbug” due to its resistance to many conventional antibiotics. MRSA infections are a global health concern. Lysostaphin’s ability to act against both methicillin-sensitive and methicillin-resistant S. aureus underscores its potential utility.
Potential Therapeutic Uses
Lysostaphin shows promise for treating various Staphylococcus aureus infections. Its application has been explored for topical skin infections and for decolonizing S. aureus from the nasal passages, a common site of bacterial carriage. Studies have shown that a single topical application can significantly reduce or eradicate S. aureus nasal colonization in animal models.
Beyond superficial infections, lysostaphin shows potential in addressing more severe systemic conditions. It has demonstrated effectiveness in treating S. aureus-mediated keratitis and endophthalmitis, which are serious eye infections. Research in animal models also indicates its capacity to clear S. aureus from the bloodstream and internal organs in cases of systemic infection like bacteremia and endocarditis.
Lysostaphin’s ability to disrupt bacterial biofilms is a key application. Biofilms are communities of bacteria encased in a protective extracellular matrix, often forming on implanted medical devices. These structures are difficult for conventional antibiotics to penetrate and eliminate, making biofilm-associated infections persistent and challenging to treat.
Lysostaphin can effectively kill S. aureus within these biofilms and also break down the extracellular matrix, making the biofilm vulnerable. This dual action helps to eradicate the sessile bacterial cells and remove the protective layer. While most effective against S. aureus, lysostaphin has also shown the ability to disrupt Staphylococcus epidermidis biofilms, although at higher concentrations.
The enzyme’s potential as a synergistic agent, working alongside traditional antibiotics, is also being investigated. Combinations of lysostaphin with antibiotics such as oxacillin, vancomycin, or linezolid have shown increased efficacy against S. aureus biofilms, including MRSA strains. This combined approach could enhance treatment outcomes and potentially allow for lower, more effective doses of antibiotics.