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

Authors

Denise K. Zinniel, University of Nebraska - LincolnFollow
Wantanee Sittiwong, Thammasat UniversityFollow
Darrell D. Marshall, Total Analysis Limited Liability CompanyFollow
Govardhan Rathnaiah, MatMaCorpFollow
Isin T. Sakallioglu, University of Nebraska - LincolnFollow
Robert Powers, University of Nebraska - LincolnFollow
Patrick H. Dussault, University of Nebraska-LincolnFollow
Raul G. Barletta, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2019

Citation

Vet. Sci. 2019, 6, 46

Comments

© 2019 by the authors.

Open access

doi:10.3390/vetsci6020046

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 effective 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 effcacy (MICs 392 to 824 μM) against Map, while a higher level of inhibition (MICs 6 to 82 μM) 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 effcacy 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.