Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/134247
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Type: | Journal article |
Title: | Rescuing tetracycline class antibiotics for the treatment of multidrug-resistant Acinetobacter baumannii pulmonary infection |
Author: | De Oliveira, D.M.P. Forde, B.M. Phan, M.-D. Steiner, B. Zhang, B. Zuegg, J. El-Deeb, I.M. Li, G. Keller, N. Brouwer, S. Harbison-Price, N. Cork, A.J. Bauer, M.J. Alquethamy, S.F. Beatson, S.A. Roberts, J.A. Paterson, D.L. McEwan, A.G. Blaskovich, M.A.T. Schembri, M.A. et al. |
Citation: | mBio, 2022; 13(1):e03517-21-1-e03517-21-14 |
Publisher: | American Society for Microbiology |
Issue Date: | 2022 |
ISSN: | 2150-7511 2150-7511 |
Editor: | Ballard, J.D. |
Statement of Responsibility: | David M.P. De Oliveira, Brian M. Forde, Minh-Duy Phan, Bernhard Steiner, Bing Zhang, Johannes Zuegg, Ibrahim M. El-deeb, Gen Li, Nadia Keller, Stephan Brouwer, Nichaela Harbison-Price, Amanda J. Cork, Michelle J. Bauer, Saleh F. Alquethamy, Scott A. Beatson, Jason A. Roberts, David L. Paterson, Alastair G. McEwan, Mark A.T. Blaskovich, Mark A. Schembri, Christopher A. McDevitt, Mark von Itzstein, Mark J. Walker |
Abstract: | Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to β-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections. Importance: Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort β-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. During the on-going COVID-19 pandemic, secondary bacterial infection by A. baumannii has been associated with a 2-fold increase in COVID-19-related mortality. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation. |
Keywords: | Animals Humans Mice Acinetobacter baumannii Acinetobacter Infections Zinc beta-Lactams Carbapenems Tetracycline Anti-Bacterial Agents Microbial Sensitivity Tests Drug Resistance, Multiple, Bacterial Pneumonia, Ventilator-Associated Pandemics Tigecycline COVID-19 |
Rights: | © 2022 De Oliveira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
DOI: | 10.1128/mbio.03517-21 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1176180 http://purl.org/au-research/grants/nhmrc/1194130 |
Published version: | http://dx.doi.org/10.1128/mbio.03517-21 |
Appears in Collections: | Microbiology and Immunology publications |
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hdl_134247.pdf | Published Version | 3.67 MB | Adobe PDF | View/Open |
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