Development of 1,2,4-Oxadiazole Antimicrobial Agents to Treat Enteric Pathogens within the Gastrointestinal Tract

Colonization of the
gastrointestinal (GI) tract with pathogenic
bacteria is an important risk factor for the development of certain
potentially severe and life-threatening healthcare-associated infections,
yet efforts to develop effective decolonization agents have been largely
unsuccessful thus far. Herein, we report modification of the 1,2,4-oxadiazole
class of antimicrobial compounds with poorly permeable functional
groups in order to target bacterial pathogens within the GI tract.
We have identified that the quaternary ammonium functionality of analogue 26a results in complete impermeability in Caco-2 cell monolayers
while retaining activity against GI pathogens Clostridioides
difficile and multidrug-resistant (MDR) Enterococcus faecium. Low compound recovery levels
after oral administration in rats were observed, which suggests that
the analogues may be susceptible to degradation or metabolism within
the gut, highlighting a key area for optimization in future efforts.
This study demonstrates that modified analogues of the 1,2,4-oxadiazole
class may be potential leads for further development of colon-targeted
antimicrobial agents.