Tuberculosis (TB) is a devastating bacterial disease for two reasons: First because there are huge numbers involved, approximately 1/3 of humanity is infected, about fifteen million people are in active disease at any one time and about two million die of TB each year. Secondly, TB is one of the most difficult bacterial infections to trea. To treat fully drug-sensitive cases of active TB takes six months and requires four different antibiotics. Multi-Drug Resistant (MDR) and eXtensively Drug Resistant (XDR) TB are resistant to some, or all, respectively, of the first line antibiotics and require drugs that are more dangerous to the patient, often must be given intravenously, and are much more expensive. There is an urgent need for faster-acting antibiotics against TB with fewer side effects and for antibiotics that are effective against MDR and XDR TB. We found that mutants unable to make biofilms are more sensitive to antibiotic in vitro during planktonic growth. Inspired by these results, we hypothesized that in vitro biofilm formation could be a unique phenotype to develop a high-throughput screen for inhibitors with novel mechanism(s) of action. A cell-based screen of 70,000 compounds for molecules that inhibit biofilm formation in Mycobacterium smegmatis yielded a number of compounds that strongly inhibit biofilm formation in Mycobacterium tuberculosis (Mtb). One candidate TCA1 has bactericidal activity against both drug susceptible and drug resistant Mtb and synergizes with rifampcin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition TCA1 showed bactericidal activity against both replicating and non-replicating Mtb in vitro. Furthermore, we have demonstrated that TCA1 is active in a Mtb mouse infection model both independently and in conjunction with INH or RIF suggesting that it is a promising lead for drug development. We propose to characterize the biological mechanism of TCA1 and carry out structure-activity relationship (SAR) studies to improve the potency and pharmacokinetics of this molecule against susceptible and drug resistant Mtb. The result will be robust lead candidates with in vivo proof of efficacy that can be further optimized and developed through future funded collaborative efforts as novel therapeutics for the treatment of TB.
The human disease tuberculosis (TB) is very difficult to treat because existing antibiotics against TB are slow acting, have deleterious side effects, and don't always work due to the evolution of resistant strains. We propose to study promising new antibiotic candidates in detail, and demonstrate proof of efficacy for at least one candidate in relevant in vivo models. These new antibiotics work differently than any now in use and our evidence is that strains resistant to extant drugs are vulnerable to the new ones.
|Vilchèze, Catherine; Copeland, Jacqueline; Keiser, Tracy L et al. (2018) Rational Design of Biosafety Level 2-Approved, Multidrug-Resistant Strains of Mycobacterium tuberculosis through Nutrient Auxotrophy. MBio 9:|
|Harbut, Michael B; Yang, Baiyuan; Liu, Renhe et al. (2018) Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity. Angew Chem Int Ed Engl 57:3478-3482|
|Vilchèze, Catherine; Weinrick, Brian; Leung, Lawrence W et al. (2018) Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence. Proc Natl Acad Sci U S A 115:1599-1604|
|Vilchèze, Catherine; Kim, John; Jacobs Jr, William R (2018) Vitamin C Potentiates the Killing of Mycobacterium tuberculosis by the First-Line Tuberculosis Drugs Isoniazid and Rifampin in Mice. Antimicrob Agents Chemother 62:|
|Liu, Renhe; Lyu, Xiaoxuan; Batt, Sarah M et al. (2017) Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. Angew Chem Int Ed Engl 56:13011-13015|
|Kerantzas, Christopher A; Jacobs Jr, William R (2017) Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application. MBio 8:|
|Vilchèze, Catherine; Hartman, Travis; Weinrick, Brian et al. (2017) Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 114:4495-4500|
|Tufariello, JoAnn M; Chapman, Jessica R; Kerantzas, Christopher A et al. (2016) Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. Proc Natl Acad Sci U S A 113:E348-57|
|Tufariello, JoAnn M; Kerantzas, Christopher A; Vilchèze, Catherine et al. (2015) The Complete Genome Sequence of the Emerging Pathogen Mycobacterium haemophilum Explains Its Unique Culture Requirements. MBio 6:e01313-15|
|Berney, Michael; Berney-Meyer, Linda; Wong, Ka-Wing et al. (2015) Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 112:10008-13|
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