Novel Amphiphilic Cyclobutene and Cyclobutane cis-C18 Fatty Acid Derivatives Inhibit Mycobacterium avium subsp. paratuberculosis Growth

Denise K. Zinniel, University of Nebraska - Lincoln
Wantanee Sittiwong, Thammasat University
Darrell D. Marshall, Total Analysis Limited Liability Company
Govardhan Rathnaiah, MatMaCorp
Isin Sakallioglu, University of Nebraska–Lincoln
Robert Powers, University of Nebraska - Lincoln
Patrick H. Dussault, University of Nebraska–Lincoln
Raul G. Barletta, University of Nebraska - Lincoln

Document Type Article

Vet. Sci. 2019, 6, 46; doi:10.3390/vetsci6020046 www.mdpi.com/journal/vetsci

Abstract

Mycobacterium avium subspecies paratuberculosis (Map) is the etiologic agent of Johne’s disease in ruminants and has been associated with Crohn’s disease in humans. An ective control of Map by either vaccines or chemoprophylaxis is a paramount need for veterinary and possibly human medicine. Given the importance of fatty acids in the biosynthesis of mycolic acids and the mycobacterial cell wall, we tested novel amphiphilic C10 and C18 cyclobutene and cyclobutane fatty acid derivatives for Map inhibition. Microdilution minimal inhibitory concentrations (MIC) with 5 or 7 week endpoints were measured in Middlebrook 7H9 base broth media. We compared the Map MIC results with those obtained previously with Mycobacterium tuberculosis and Mycobacterium smegmatis. Several of the C18 compounds showed moderate ecacy (MICs 392 to 824 M) against Map, while a higher level of inhibition (MICs 6 to 82 M) was observed for M. tuberculosis for select analogs from both the C10 and C18 groups. For most of these analogs tested in M. smegmatis, their ecacy decreased in the presence of bovine or human serum albumin. Compound 5 (OA-CB, 1-(octanoic acid-8-yl)-2-octylcyclobutene) was identified as the best chemical lead against Map, which suggests derivatives with better pharmacodynamics may be of interest for evaluation in animal models.