A Human Biofilm-Disrupting Monoclonal Antibody Potentiates Antibiotic Efficacy in Rodent Models of both Staphylococcus aureus and Acinetobacter baumannii Infections [PublishAheadOfPrint]

Many serious bacterial infections are antibiotic-refractory due to biofilm formation. A key structural component of biofilm is extracellular DNA which is stabilized by bacterial proteins, including those from the DNABII family. TRL1068 is a high affinity human monoclonal antibody against a DNABII epitope conserved across both gram-positive and gram-negative bacterial species. In the current study, the efficacy of TRL1068 for disruption of biofilm was demonstrated in vitro in the absence of antibiotics by scanning electron microscopy. In vivo efficacy of this antibody was investigated in a well-characterized catheter-induced aortic valve infective endocarditis model in rats infected with a methicillin-resistant Staphylococcus aureus (MRSA) strain with the ability to form thick biofilm, obtained from the blood of a patient with a persistent clinical infection. Animals were treated with vancomycin alone or in combination with TRL1068. MRSA burdens in cardiac vegetations, and within intracardiac catheters, kidneys, spleen and liver showed a significant reduction in the combination arm vs vancomycin alone (p<0.001). A trend towards mortality reduction was also observed (p=0.09). In parallel, in vivo efficacy of TRL1068 against a multi-drug resistant clinical Acinetobacter baumannii isolate was explored using an established skin and soft tissue catheter-related biofilm infection mouse model. Catheter segments infected with A. baumannii were implanted subcutaneously in mice; animals were treated with imipenem alone or in combination with TRL1068. The combination showed a significant reduction in catheter-adherent bacteria vs. antibiotic alone (p<0.001). TRL1068 shows excellent promise as an adjunct to standard-of-care antibiotics for a broad range of difficult-to-treat bacterial infections.

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