Disruption of nontuberculous mycobacteria biofilms induces a highly vulnerable to antibiotic killing phenotype
Nikola Kurbatfinski,
Preston J. Hill,
Noah Tobin,
Cameron N. Kramer,
Joseph Wickham,
Steven D. Goodman,
Luanne Hall-Stoodley,
Lauren O. Bakaletz
Affiliations
Nikola Kurbatfinski
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
Preston J. Hill
Department of Microbial Infection and Immunity, The Ohio State University, 460 W 12th Ave., Columbus, OH, 43210, USA
Noah Tobin
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
Cameron N. Kramer
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
Joseph Wickham
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
Steven D. Goodman
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
Luanne Hall-Stoodley
Department of Microbial Infection and Immunity, The Ohio State University, 460 W 12th Ave., Columbus, OH, 43210, USA
Lauren O. Bakaletz
Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Corresponding author. Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
Objectives: Structural or mucus hypersecretory pulmonary diseases such as cystic fibrosis (CF), wherein viscous mucus accumulates and clearance functions are impaired, predispose people to lung infection by inhaled bacteria that form biofilm aggregates. Nontuberculous mycobacteria (NTM), primarily Mycobacterium abscessus and Mycobacterium avium, are the growing cause of these lung infections and are extremely challenging to treat due to antibiotic recalcitrance. Better therapeutic approaches are urgently needed. We developed a humanized monoclonal antibody (HuTipMab) directed against a biofilm structural linchpin, the bacterial DNABII proteins, that rapidly disrupts biofilms and generates highly vulnerable newly released bacteria (NRel). Methods: HuTipMab's ability to recognize HupB, NTM's DNABII homologue was determined by ELISA. Relative ability of HuTipMab to disrupt biofilms formed by lab-passaged and clinical isolates of NTM was assessed by CLSM. Relative sensitivity of NTM NRel to antibiotic killing compared to when grown planktonically was evaluated by plate count. Results: HuTipMab recognized HupB and significantly disrupted NTM biofilms in a time- and dose-dependent manner. Importantly, NTM NRel of lab-passaged and clinical isolates were now highly sensitive to killing by amikacin and azithromycin. Conclusions: If successful, this combinatorial treatment strategy would empower existing antibiotics to more effectively kill NTM newly released from a biofilm by HuTipMab and thereby both improve clinical outcomes and perhaps decrease length of antibiotic treatment for people that are NTM culture-positive.
