<i>Clostridioides difficile</i> is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. <i>C. difficile</i> 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 <i>C. difficile</i> infection, antibiotics that selectively target <i>C. difficile</i> over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against <i>C. difficile</i>. The structure-activity relationship of 108 analogues of isonicotinamide <b>4</b>, a compound that is equally active against methicillin-resistant <i>Staphylococcus aureus</i> and <i>C. difficile</i>, was investigated. Introduction of the picolinamide core as exemplified by analogue <b>87</b> resulted in exquisite potency and selectivity against <i>C. difficile</i>. The ability of the picolinamide class to selectively target <i>C. difficile</i> and to prevent gut dysbiosis holds promise for the treatment of recurrent <i>C. difficile</i> infection.