TY - JOUR
T1 - Novel amphiphilic cyclobutene and cyclobutane cis-C18 fatty acid derivatives inhibit Mycobacterium avium subsp. paratuberculosis growth
AU - Zinniel, Denise K.
AU - Sittiwong, Wantanee
AU - Marshall, Darrell D.
AU - Rathnaiah, Govardhan
AU - Sakallioglu, Isin T.
AU - Powers, Robert
AU - Dussault, Patrick H.
AU - Barletta, Raúl G.
N1 - Funding Information:
Funding: This research was funded by NU Ventures University Technology Development Corporation, grant number 2132340015, entitled “Fatty Acid Analogs as a New Class of Antimicrobial Agents” and the University of Nebraska Research Council, grant number IC-2592, entitled “Investigations of Potential New Therapeutics for Multidrug Resistant Tuberculosis”. This work was also supported in part by funding from the University of Nebraska Redox Biology Center (P30 GM103335, NIGMS), and the Nebraska Center for Integrated Biomolecular Communication (P20 GM113126, NIGMS). The research was performed in facilities renovated with support from the National Institutes of Health (RR015468-01).
Publisher Copyright:
© 2019 by the authors.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - Cyclobutane derivatives
KW - Cyclobutene derivatives
KW - Growth inhibition
KW - Mycobacterium avium subsp. paratuberculosis
KW - cis-C fatty acids
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U2 - 10.3390/vetsci6020046
DO - 10.3390/vetsci6020046
M3 - Article
C2 - 31137605
AN - SCOPUS:85067062673
SN - 2306-7381
VL - 6
JO - Veterinary Sciences
JF - Veterinary Sciences
IS - 2
M1 - 46
ER -