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

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 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.

Cyclobutanes in Small‐Molecule Drug Candidates

“…The authors synthesized carbocyclic derivatives of decanoic and oleic acids with different functionalities. The cyclobutane derivatives showed significant In a similar study performed by the same group, Zinniel et al [125] identified that the same group of cyclobutane derivatives of decanoic and oleic acids exhibit similar behaviour towards mycobacterium avium paratuberculosis (Map). While both C 10 and C 18 derivatives showed efficacy in the Mtb study, only C 18 analogues showed significant activity efficacy against Map.…”

“…The cyclobutane derivatives showed significant inhibitory anti‐mycobacterial activity against Mtb , 69 and 70 (Figure 35) appeared more active than clinically used TB drug D ‐cycloserine (CDC1551 & H37Rv week MIC: 4/(39) and 8/(78) μM, respectively) and 69 proved equally, if not more potent than isoniazid (CDC1551 & H37Rv week MIC: 4/(29) and 8/(58) μM, respectively). In a similar study performed by the same group, Zinniel et al [125] . identified that the same group of cyclobutane derivatives of decanoic and oleic acids exhibit similar behaviour towards mycobacterium avium paratuberculosis (Map) .…”

“…However, its unique structure and properties as demonstrated in this review and continuous efforts in synthesis methods might render it a prominent member in the medicinal chemist's toolbox in the not-toodistant future. Absorption and plasma levels Increased NS5B Thumb pocket 1 inhibitor [102,103] Hepatitis C 5-HT6R antagonists [117] Schizophrenia Cytotoxicity Lowered Anti-leishmanial [120] Visceral Leishmaniasis Mycobacterium toxicity Increased Anti Mtb and Map mycobacterials [124,125]…”

Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue

“…In summary, we report the elucidation of a probable MoA for DA-CB, an antimycobacterial fatty acid analogue. 15,16 A multiomics approach that combined lipidomics, metabolomics, and proteomics provided numerous, reinforcing, and complementary results. Our integrated metabolomics, lipidomics, and proteomics analysis identified alterations in the FAS-II system, specifically in the terminal steps of mycolic acid biosynthesis.…”

“…14 In this regard, we previously synthesized and investigated 11 fatty acid analogues, 6 of which showed minimum inhibitory concentration (MIC) values equivalent to or better than the second-line TB drug D-cycloserine (DCS). 15,16 The fatty acid motifs were based on frameworks derived from decenoic acid (C 10 ), oleic acid, or elaidic acid (both C 18 ). Several of these fatty acid analogues displayed low micromolar MIC values against various Mtb strains, where 8-(2-cyclobuten-1-yl)octanoic acid (DA-CB), a cyclobutenecontaining analogue of decanoic acid, exhibited activity similar to that of the TB drugs, isoniazid (INH) and ethionamide (ETH).…”