Open AccessStructure–Activity Relationship for the Picolinamide Antibacterials that Selectively Target Clostridioides difficile
Author(s) -
Enrico Speri,
Yuanyuan Qian,
Jeshina Janardhanan,
Cesar Masitas,
Elena Lastochkin,
Stefania De Benedetti,
Weitao Man,
Valerie A. Schroeder,
William R. Wolter,
Allen G. Oliver,
Jed F. Fisher,
Shahriar Mobashery,
Mayland Chang
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00135
Subject(s) - clostridioides , antibiotics , chemistry , microbiology and biotechnology , pharmacology , biology
Clostridioides difficile is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. C. difficile is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics. To address the urgent need for treating recurrent C. difficile infection, antibiotics that selectively target C. difficile over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against C. difficile . The structure-activity relationship of 108 analogues of isonicotinamide 4 , a compound that is equally active against methicillin-resistant Staphylococcus aureus and C. difficile , was investigated. Introduction of the picolinamide core as exemplified by analogue 87 resulted in exquisite potency and selectivity against C. difficile . The ability of the picolinamide class to selectively target C. difficile and to prevent gut dysbiosis holds promise for the treatment of recurrent C. difficile infection.