Bacteriophage-derived endolysins to target gram-negative bacteria

Bacteriophage-encoded endolysins (lysins) have emerged as a novel class of antibacterial agents to combat the surging antibiotic resistance. Lysins have specific structures and mechanisms to exert antibacterial effect against both Gram-positive (G+ve) and Gram-negative (G-ve) bacteria. However, its use against G-ve bacteria is limited because the outer membrane (OM) of G-ve bacteria hinders the permeation of exogenously applied lysins. Besides identifying lysins with intrinsic OM permeability, several other approaches including combining lysins with outer membrane permeabilizers (OMPs), protein engineering and formulating with nanocarriers have been proposed to enhance the permeability and activity of lysins. In the present review, we summarize strategies that have been developed to enable lysins to target G-ve bacteria in the past decade. While lysins demonstrates clear potential in managing bacterial infections caused by the drug-resistant G-ve bacteria, there are still challenges hindering their translation into clinical settings, including safety issues with OMP use, low efficiency against stationary phase bacteria and problems in stability. The applicability of protein engineering and formulation sciences to improve enzyme stability, and combination therapy with other classes of antibacterial agents to maximize the therapeutic potential have also been reviewed.