Publications

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.┬átuberculosis 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…

Neutrophil-plasmacytoid dendritic cell interaction leads to production of type I IFN in response to Mycobacterium tuberculosis.

Date Published: March 31, 2024
Mycobacterium tuberculosis (Mtb) can cause a latent infection that sometimes progresses to clinically active tuberculosis (TB). Type I interferons (IFN-I) have been implicated in initiating the progression from latency to active TB, in part because IFN-I stimulated genes are the earliest genes to be upregulated in patients as they advance…

Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Date Published: February 9, 2024
Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen…
Courtesy of the U.S. National Library of Medicine