The Anti-Staphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood to Potentiate MRSA Bacteriolysis [Experimental Therapeutics]

Bacteriophage-derived lysins are cell wall hydrolytic enzymes which represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile CF-301's activity in a clinically relevant milieu, we assessed its in vitro activity in human blood vs. in a conventional testing medium (cation-adjusted Mueller Hinton Broth [caMHB]). CF-301 exhibited substantially greater potency (32-≥100-fold) in human blood vs. caMHB in three standard microbiologic testing formats (e.g. broth dilution MICs, checkerboard synergy and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic MRSA strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics, at > 100-fold lower lysin doses in the rabbit vs the rat model. The unique properties of CF-301 which enable bactericidal potentiation of antimicrobial activity via activation of 'latent' host factors in human blood may have important therapeutic implications for the durable improvements in clinical outcomes of serious, antibiotic-resistant staphylococcal infections.

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