Mycobacterium tuberculosis (Mtb)?the causative agent of the disease tuberculosis (TB)? has afflicted humans for thousands of years. It is the leading worldwide bacterial cause of death. Treatment requires multiple antibiotics for at least six months. In addition, there is rising prevalence of extensively drug resistant isolates, and the pipeline for new anti-mycobacterials is inadequate. Mtb?s success rests upon the fact that it grows in macrophages. This raises the possibility that host-directed therapeutics (HDTs) in combination with antibacterials might shorten treatment courses or reduce immunopathology. Here, we investigate whether drugs that block host fatty acid b?-oxidation (FAO) can treat TB. This proposal is based upon our unexpected discoverythatFAOinhibitors,includingtrimetazidinewhichisapprovedforclinicaluse,blocktheintracellular growthofMtb.WehypothesizethatFAOinhibitorspreventMtbfromgrowingwithinmacrophagesbyinducing cellular oxidative stress, activating autophagy, and promoting pro-inflammatory cytokine production. We will investigatetheanti-mycobacterialactivityofthesecompounds,definetheirantimicrobialmechanismofaction, andevaluatetheiranti-tuberculousefficacyinvivo.OurproposedstudieswillestablishwhetherFAOisahost pathwaytotargetforTBtreatment.Inaddition,thesestudieswillcontributetoourbasicunderstandingofMtb pathogenesis. Given the favorable pharmacokinetics and safety profiles of FAO inhibitors, our findings could rapidlytranslatetopatientswithmulti-drugresistant(MDR)TB.
Mycobacterium tuberculosis (Mtb)- the causative agent of tuberculosis (TB)- is the leading worldwide bacterial cause of death. We will determine how compounds that inhibit host fatty acid ?-oxidation inhibit the intracellular growth of Mtb in macrophages and evaluate their efficacy in vivo. Given that these compounds are already used clinically, our studies could rapidly lead to new TB therapies.
| Upadhyay, S; Mittal, E; Philips, J A (2018) Tuberculosis and the art of macrophage manipulation. Pathog Dis 76: |
| Frankfater, Cheryl; Jiang, Xuntian; Hsu, Fong-Fu (2018) Characterization of Long-Chain Fatty Acid as N-(4-Aminomethylphenyl) Pyridinium Derivative by MALDI LIFT-TOF/TOF Mass Spectrometry. J Am Soc Mass Spectrom 29:1688-1699 |
