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

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 e...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2017-10, Vol.61 (10)
Main Authors: Xiong, Yan Q, Estellés, Angeles, Li, L, Abdelhady, W, Gonzales, R, Bayer, Arnold S, Tenorio, Edgar, Leighton, Anton, Ryser, Stefan, Kauvar, Lawrence M
Format: Article
Language:English
Subjects:
Acinetobacter baumannii
Acinetobacter Infections
Anti-Bacterial Agents
Antibodies, Monoclonal
Biofilms
Endocarditis
Experimental Therapeutics
Methicillin-Resistant Staphylococcus aureus
Staphylococcal Infections
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Summary: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 present study, the efficacy of TRL1068 for the disruption of biofilm was demonstrated in the absence of antibiotics by scanning electron microscopy. The efficacy of this antibody was investigated in a well-characterized catheter-induced aortic valve infective endocarditis model in rats infected with a methicillin-resistant (MRSA) strain with the ability to form thick biofilms, obtained from the blood of a patient with 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 significant reductions in the combination arm versus vancomycin alone ( < 0.001). A trend toward mortality reduction was also observed ( = 0.09). In parallel, the efficacy of TRL1068 against a multidrug-resistant clinical isolate was explored by using an established mouse model of skin and soft tissue catheter-related biofilm infection. Catheter segments infected with were implanted subcutaneously into mice; animals were treated with imipenem alone or in combination with TRL1068. The combination showed a significant reduction of catheter-adherent bacteria versus the antibiotic alone ( < 0.001). TRL1068 shows excellent promise as an adjunct to standard-of-care antibiotics for a broad range of difficult-to-treat bacterial infections.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00904-17