Publications

Tuberculosis in otherwise healthy adults with inherited TNF deficiency.

Date Published: September 28, 2024
Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal…

Exploiting cAMP signaling in Mycobacterium tuberculosis for drug discovery.

Date Published: September 14, 2024
Mycobacterium tuberculosis (Mtb) replicates within host macrophages by adapting to the stressful and nutritionally constrained environments in these cells. Exploiting these adaptations for drug discovery has revealed that perturbing cAMP signaling can restrict Mtb growth in macrophages. Specifically, compounds that agonize or stimulate the bacterial enzyme, Rv1625c/Cya, induce cAMP synthesis…

Combating antimicrobial resistance in malaria, HIV and tuberculosis.

Date Published: June 15, 2024
Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it…

Weak links: Advancing target-based drug discovery by identifying the most vulnerable targets.

Date Published: May 10, 2024
Mycobacterium tuberculosis remains the most common infectious killer worldwide despite decades of antitubercular drug development. Effectively controlling the tuberculosis (TB) pandemic will require innovation in drug discovery. In this review, we provide a brief overview of the two main approaches to discovering new TB drugs-phenotypic screens and target-based drug discovery-and…

A dual-targeting succinate dehydrogenase and FF-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis.

Date Published: April 18, 2024
Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments,…

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis.

Date Published: April 3, 2024
The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286…

Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Date Published: April 2, 2024
Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here…
Courtesy of the U.S. National Library of Medicine