As highlighted in the 'Bad Bugs, No Drugs'campaign by the Infectious Diseases Society of America, """"""""There simply aren't enough new drugs in the pharmaceutical pipeline to keep pace with drug-resistant bacterial infections, so-called 'superbugs'."""""""" Numerous hospitals worldwide have experienced outbreaks caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, three of the 6 top-priority dangerous """"""""ESKAPE"""""""" pathogens that require the most urgent attention to discover new antibiotics. Sadly, no novel antibiotics against these Gram-negative 'superbugs'will be available for many years to come. Polymyxins (i.e. polymyxin B and colistin) are now being used as the last-line therapy for these very problematic MDR pathogens. Most unfortunately, the emergence of polymyxin resistance has been increasingly reported recently. In essence, resistance to polymyxins implies a total lack of antibiotics for treatment of life-threatening infections caused by these pandrug-resistant (PDR) Gram-negative bacteria. Research Design: This project will apply systems pharmacology to antibiotic pharmacokinetics/pharmacodynamics (PK/PD) to identify novel polymyxin combinations with FDA-approved nonantibiotic drugs against PDR P. aeruginosa, A. baumannii and K. pneumoniae. Our over-arching hypothesis is that the identified polymyxin-nonantibiotic combinations will synergistically kill Gram-negative 'superbugs'with minimal development of resistance, and integration of systems pharmacology with antimicrobial PK/PD modeling will elucidate the underlying mechanism(s) of the synergistic interaction between host-pathogen-drug.
Our specific aims are to: (1) Identify novel polymyxin-nonantibiotic combinations against pandrug-resistant P. aeruginosa, A. baumannii and K. pneumoniae;(2) Investigate the in vitro PK/PD of active polymyxin-nonantibiotic combinations;(3) Evaluate the synergistic killing and suppression of polymyxin resistance by the active combinations over 2-week treatment using hollow fiber infection model and conduct omics studies;(4) Demonstrate proof-of-concept for the most active combinations using mouse infection models and conduct integrated omics studies to understand the host-pathogen-drug interactions;and (5) Conduct systems pharmacology network analysis and PK/PD mathematical modeling on the polymyxin- nonantibiotic combinations. Transcriptomics, proteomics and metabolomics will be utilized to investigate the interaction between host, pathogen and drug. Together, these studies will identify the best polymyxin-nonantibiotic combination (plus one backup) for further pharmacological evaluations. Significance: This project holds great promise for development of novel polymyxin combinations. As all drugs have already been approved by FDA, our multi-disciplinary approach will provide a fast-track and cost-effective solution to combat these very problematic Gram-negative 'superbugs'. Overall, this project targets the urgent global unmet medical need, lack of new antibiotics.

Public Health Relevance

The world is facing an enormous and growing threat from the emergence of bacterial 'superbugs'Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae that are resistant to all antibiotics, while no novel antibiotics are in current drug discovery pipeline. As described in the 'Bad Bugs, No Drugs'paper published by the Infectious Diseases Society of America, as antibiotic discovery stagnates, a public health crisis brews. This project will employ antimicrobial PK/PD and systems pharmacology to develop novel polymyxin combinations and responds to the recent global call for discovery of new antibiotics: The 10 x '20 Initiative.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-FDS-M (J2))
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Xu, Zuoyu
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Monash University
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Lu, Xiaoxi; Chan, Ting; Xu, Chenghao et al. (2016) Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins. J Antimicrob Chemother 71:403-12
Maifiah, Mohd Hafidz Mahamad; Cheah, Soon-Ee; Johnson, Matthew D et al. (2016) Global metabolic analyses identify key differences in metabolite levels between polymyxin-susceptible and polymyxin-resistant Acinetobacter baumannii. Sci Rep 6:22287
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