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Open AccessFeature PaperArticle

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

1
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska–Lincoln, Lincoln, NE 68583, USA
2
Department of Chemistry, Faculty of Science and Technology, Thammasat University, Rangsit Campus, Phaholyothin Rd., Klong Luang, Pathum Thani 12121, Thailand
3
Total Analysis Limited Liability Company, Detroit, MI 48204, USA
4
Materials and Machines Corporation (MatMaCorp), Lincoln, NE 68507, USA
5
Department of Chemistry, University of Nebraska–Lincoln, Lincoln, NE 68588, USA
6
Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
*
Author to whom correspondence should be addressed.
Vet. Sci. 2019, 6(2), 46; https://doi.org/10.3390/vetsci6020046
Received: 29 April 2019 / Revised: 17 May 2019 / Accepted: 21 May 2019 / Published: 24 May 2019
(This article belongs to the Special Issue Mycobacterial Diseases in Animals)
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 efficacy (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 efficacy 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. View Full-Text
Keywords: cis-C18 fatty acids; cyclobutane derivatives; cyclobutene derivatives; growth inhibition; Mycobacterium avium subsp. paratuberculosis cis-C18 fatty acids; cyclobutane derivatives; cyclobutene derivatives; growth inhibition; Mycobacterium avium subsp. paratuberculosis
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Zinniel, D.K.; Sittiwong, W.; Marshall, D.D.; Rathnaiah, G.; Sakallioglu, I.T.; Powers, R.; Dussault, P.H.; Barletta, R.G. Novel Amphiphilic Cyclobutene and Cyclobutane cis-C18 Fatty Acid Derivatives Inhibit Mycobacterium avium subsp. paratuberculosis Growth. Vet. Sci. 2019, 6, 46.

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