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

Abstract

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 vitro in the absence of antibiotics by scanning electron microscopy. The 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 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 (P < 0.001). A trend toward mortality reduction was also observed (P = 0.09). In parallel, the in vivo efficacy of TRL1068 against a multidrug-resistant clinical Acinetobacter baumannii isolate was explored by using an established mouse model of skin and soft tissue catheter-related biofilm infection. Catheter segments infected with A. baumannii 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 (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.

Keywords: Acinetobacter; MRSA; biofilms; infective endocarditis; monoclonal antibody; skin and soft tissue infection.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Disruption of biofilms in vitro. Bacterial biofilm was formed on conical plastic pegs in a 96-well format. Pegs were treated with IgG isotype control MAb (left) or TRL1068 (right) at 1.2 μg/ml for 12 h. Adherent A. baumannii bacterial cells were visualized by SEM at ×5,000 and ×10,000 magnifications. TRL1068-treated pegs have a thinner biofilm and bacterial cells are less densely packed than on the control pegs.

FIG 2

In vivo efficacy of TRL1068 with or without vancomycin (VAN) in a rat infective endocarditis model due to MRSA. Median and quartile values are shown, with outliers being denoted by circles. (A) Bacterial burdens of vegetation at the primary site of infection were significantly reduced by 2 logs when TRL1068 was added to vancomycin. (B) An ∼1-log reduction of infection was seen at secondary infection sites. (C) Combination therapy resulted in reduced mortality.

FIG 3

In vivo efficacy of TRL1068 with or without imipenem (IPM) in a murine catheter-related skin and soft tissue infection model due to a multidrug-resistant A. baumannii strain. Median and quartile values are shown, with outliers being denoted by circles. TRL1068 potentiates imipenem activity against A. baumannii (106 CFU). (A) Imipenem at 100 mg/kg BID; (B) imipenem at 150 mg/kg QID. For data in both panels, TRL1068 was given at 15 mg/kg on days 1 and 4; the control includes an isotype control nonimmune MAb.

References

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