The microorganisms that are mainly involved in the resistance process are the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) emphasizing their ability to escape from common antibacterial treatments. It has been significant public concern that the absence of progress in developing novel therapeutics to treat multidrug-resistant (MDR) infections caused by Gram-negative bacteria. We identified that a new pleuromutilin analog exhibited bactericidal activity against E. coli and Klebsiella pneumoniae with the MIC values of 0.78 and 0.65 g/mL, respectively. It is a very interesting fact that functionalizations of the carbonyl (C3-position) and the side chain (C14-position) of pleuromutilin can extend the spectrum of activity focused against Gram-negative bacteria. A pleuromutilin analog has been developed into a phase II clinical drug via systemic administration for the treatment of complicated skin and soft tissue infection (cSSTI) caused by Gram-positive pathogens, however, development of pleuromutilin analogs for Gram-negative bacterial infections has never been the subject of antibacterial researches. Our rationale for this application is that successful completion of the proposed projects will provide the critical date t perform extensive structure activity relationship studies of pleuromutilin derivatives for improvin PK/PD and in vivo efficacy. In order to accomplish the research projects proposed here, the PI has assembled an interdisciplinary consortium capable of fulfilling the goals of this proposal.

Public Health Relevance

Infections caused by MDR-Gram-negative pathogens, such as Klebsiella pneumonia, Enterobacteriaceae, Acinetobacter baumanii and Pseudomonas aeruginosa are difficult to treat. The absence of progress in developing novel therapeutics to treat such infections is a significant public concern. The long term goal of the proposed research project is to develop a new pleuromutilin analog to combat MDR-Gram-negative pathogens via intravenous administration.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Xu, Zuoyu
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University of Tennessee Health Science Center
Schools of Pharmacy
United States
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Lemieux, Maddie R; Siricilla, Shajila; Mitachi, Katsuhiko et al. (2018) An antimycobacterial pleuromutilin analogue effective against dormant bacilli. Bioorg Med Chem 26:4787-4796
Mitachi, Katsuhiko; Yun, Hyun Gi; Kurosu, Sara M et al. (2018) Novel FR-900493 Analogues That Inhibit the Outgrowth of Clostridium difficile Spores. ACS Omega 3:1726-1739
Siricilla, Shajila; Mitachi, Katsuhiko; Yang, Junshu et al. (2017) A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii. J Med Chem 60:2869-2878
Mitachi, Katsuhiko; Kurosu, Yuki E; Hazlett, Brandon T et al. (2016) Oxyma-based phosphates for racemization-free peptide segment couplings. J Pept Sci 22:186-91
Mitachi, Katsuhiko; Sharma Gautam, Lekh Nath; Rice, Jeffrey H et al. (2016) Structure determination of lipopeptides from Mycobacterium avium subspecies paratuberculosis and identification of antigenic lipopeptide probes. Anal Biochem 505:29-35