US-12616691-B2 - Use of fatty acid oxidation inhibitors as antimicrobials

Abstract

Methods of using small molecule inhibitors of fatty acid oxidation (FAO) as antimicrobials against intracellular Mycobacteria are disclosed. FAO inhibitors including etomoxir, trimetazidine, oxfenicine perhexeline and/or can be used alone, or in combination with known as antimycobacterial agents against intracellular Mycobacteria.

Inventors

• Jennifer A. Philips
• Kathryn Moore
• Pallavi Chandra
• Mireille Ouimet

Assignees

• WASHINGTON UNIVERSITY IN ST. LOUIS
• NEW YORK UNIVERSITY

Dates

Publication Date

20260505

Application Date

20230621

Claims (13)

1. 1 . A method of treating a Mycobacteria infection in a subject in need thereof, the method comprising administering a dosage of trimetazidine to the subject to achieve a concentration ranging from about 1 nM to about 500 nM to reduce fatty acid oxidation by inhibiting 3-ketoacyl-CoA thiolase.
2. 2 . The method as set forth in claim 1 , wherein the subject in need thereof has or is suspected of having Mycobacterium tuberculosis (Mtb), multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), Mycobacterium abscessus, Mycobacterium fortuitum , and Mycobacterium chelonae.
3. 3 . The method as set forth in claim 1 further comprising administering the trimetazidine in combination with at least one additional antimycobacterial agent.
4. 4 . The method as set forth in claim 3 , wherein the antimycobacterial agent is selected from the group consisting of isoniazid (INH), rifampin, ethambutol, pyrazinamide, streptomycin, amikacin, capreomycin, bedaquiline, delamanid, a fluoroquinolone, linezolid, ethionamide, prothinamide, cycloserine, terizidone, p-aminosalicylic acid, clofazamine, amoxicillin and clavulanate, thioacetozone, clarithromycin, and imipenem.
5. 5 . The method as set forth in claim 1 further comprising administering the trimetazidine in combination with at least one additional agent selected from the group consisting of metformin, statins, valproic acid, carbamezapine, vorinostat, phenylbutyrate, rapamycin, imatinib, desipramine, alisporivir, COX inhibitors, zileuton, bestatin, sildenafin, and pentyoxyfylline.
6. 6 . A method of inhibiting intracellular growth of Mtb in a subject in need thereof, the method comprising administering a dosage of trimetazidine to the subject to achieve a concentration ranging from about 1 nM to about 500 nM to reduce fatty acid oxidation by inhibiting 3-ketoacyl-CoA thiolase.
7. 7 . The method as set forth in claim 6 , wherein the subject in need thereof has or is suspected of having Mycobacterium tuberculosis (Mtb), multidrug-resistant tuberculosis (MDR-TB), and extensively drug-resistant tuberculosis (XDR-TB).
8. 8 . The method as set forth in claim 6 further comprising administering the trimetazidine in combination with at least one additional antimycobacterial agent.
9. 9 . The method as set forth in claim 8 , wherein the antimycobacterial agent is selected from the group consisting of isoniazid (INH), rifampin, ethambutol, pyrazinamide, streptomycin, amikacin, capreomycin, bedaquiline, delamanid, a fluoroquinolone, linezolid, ethionamide, prothinamide, cycloserine, terizidone, p-aminosalicylic acid, clofazamine, amoxicillin and clavulanate, thioacetozone, clarithromycin, and imipenem.
10. 10 . The method as set forth in claim 6 further comprising administering the trimetazidine in combination with at least one additional agent selected from the group consisting of metformin, statins, valproic acid, carbamezapine, vorinostat, phenylbutyrate, rapamycin, imatinib, desipramine, alisporivir, COX inhibitors, zileuton, bestatin, sildenafin, and pentyoxyfylline.
11. 11 . A method of inhibiting intracellular growth of Mycobacterium abscessus in a subject in need thereof, the method comprising administering a dosage of trimetazidine to the subject to achieve a concentration ranging from about 1 nM to about 500 nM to reduce fatty acid oxidation by inhibiting 3-ketoacyl-CoA thiolase.
12. 12 . The method as set forth in claim 11 further comprising administering the trimetazidine in combination with at least one additional antimycobacterial agent.
13. 13 . The method as set forth in claim 11 further comprising administering the trimetazidine in combination with at least one additional agent selected from the group consisting of metformin, statins, valproic acid, carbamezapine, vorinostat, phenylbutyrate, rapamycin, imatinib, desipramine, alisporivir, COX inhibitors, zileuton, bestatin, sildenafin, and pentyoxyfylline.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 16/979,443, filed on Sep. 8, 2020, which is a U.S. National Phase Application of PCT/US2019/022457 (published as WO 2019/178472), filed on Mar. 15, 2019, which claims priority to U.S. Provisional Application Ser. No. 62/644,105, filed on Mar. 16, 2018, the disclosures of which are hereby incorporated by reference herein in their entireties. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under AI105298, AI087682, HL108182, HL119047 and AI128427 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE DISCLOSURE The present disclosure relates generally to the use of small molecule inhibitors of fatty acid oxidation (FAO) as antimicrobials. Particularly, the present disclosure is directed to the use of etomoxir, trimetazidine and/or perhexeline as antimicrobials against intracellular Mycobacteria. Mycobacterium tuberculosis (Mtb) complex causes one of the world's deadliest infections. Particularly, worldwide, there are more than 10 million new cases of tuberculosis annually, resulting in 1.8 million deaths. Mtb survives within macrophages by preventing its own delivery to the degradative, phagolysosomal compartment. Particularly, Mtb induces host microRNA-33 (miR-33), which promotes the intracellular survival of Mtb by inhibiting autophagy and reprograming host lipid metabolism in Mtb-infected macrophages. Autophagy promotes degradation of intracellular bacteria through autophagosomes that deliver bacteria to lysosomes, a process termed xenophagy. Xenophagy does not effectively clear Mtb unless it is activated pharmacologically or by pro-inflammatory cytokines. While treatments have been developed, Mtb has responded by morphing into multidrug-resistant tuberculosis (MDR-TB), which is resistant to first line anti-TB drugs (e.g., isoniazid and rifampin). Mtb has further developed into extensively drug-resistant tuberculosis (XDR-TB). XDR-TB is caused by bacteria that are resistant to first- and second-line anti-TB drugs, and threatens a global epidemic. Particularly, MDR-TB is an increasing problem, with more than 500,000 cases in 2015, and XDR-TB is found in over 100 countries. Further, the treatment courses are long, complicated, and toxic. Mycobacterium abscessus complex is a group of multidrug-resistant nontuberculous species. Nontuberculous species can cause pulmonary disease resembling tuberculosis, skin and soft tissue infections, central nervous system infections, bacteremia, and ocular and other infections. M. abscessus complex is difficult to treat because of antimicrobial drug resistance, and is a major problem in patients with Cystic Fibrosis. Host directed therapeutics (HDTs) may engender less resistance than drugs that directly target bacteria and might modulate immunopathology in a beneficial way. By targeting infected host cells, HDTs might also effectively eradicate slowly growing or non-replicating bacilli, thereby shortening therapy when used in combination with conventional antibiotics. Accordingly, there exists a need for developing HDTs for tuberculosis (TB) and nontuberculous Mycobacteria infections. BRIEF DESCRIPTION The present disclosure is generally directed to the use of the FAO inhibitors as antimicrobials against intracellular Mycobacteria infections. FAO inhibitors are particularly useful for treating Mycobacterium tuberculosis (Mtb) infections and nontuberculous Mycobacteria infections. In some embodiments, the FAO inhibitors are incorporated into compositions with pharmaceutically acceptable carriers. In some embodiments, the FAO inhibitors are used in combination with other therapeutics, such as other known anti-mycobacterial agents. In one aspect, the present disclosure is directed to a method of treating Mycobacteria infection in a subject in need thereof, the method comprising administering a fatty acid oxidation (FAO) inhibitor to the subject. In one embodiment, the Mycobacteria is Mycobacterium tuberculosis complex. In one embodiment, the Mycobacteria is Mycobacterium abscessus complex. In another aspect, the present disclosure is directed to a method of inhibiting intracellular growth of Mycobacterium in a subject in need thereof, the method comprising administering a fatty acid oxidation (FAO) inhibitor to the subject. In one embodiment, the Mycobacteria is Mycobacterium tuberculosis complex. In one embodiment, the Mycobacteria is Mycobacterium abscessus complex. BRIEF DESCRIPTION OF THE DRAWINGS The disclosure will be better understood, and features, aspects and advantages other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such detailed description makes reference to the following drawings, wherein: FIG. 1 depicts the carnitine shuttle and FAO. Long chain fatty acids are transported across the plasma m