Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements.

Date Published: September 20, 2022
A challenge in tuberculosis treatment regimen design is the necessity to combine three or more antibiotics. We narrow the prohibitively large search space by breaking down high-order drug combinations into drug pair units. Using pairwise in vitro measurements, we train machine learning models to predict higher-order combination treatment outcomes in the…

How drug resistance has shaped anti-tubercular drug discovery.

Date Published: September 9, 2022
Drug resistance is an increasing problem for the treatment of tuberculosis. The prevalence of clinical isolates with pre-existing resistance needs to be considered in any drug discovery program. Non-specific mechanisms of resistance such as increased efflux or decreased permeability need to be considered both in developing individual drug candidates and…

Iron limitation in M. tuberculosis has broad impact on central carbon metabolism.

Date Published: July 9, 2022
Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify inhibitors…

CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis.

Date Published: June 30, 2022
Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Treatment efficacy is limited by Mtb’s intrinsic drug resistance, as well as its ability to evolve acquired resistance to all antituberculars in clinical use. A deeper understanding of the bacterial pathways that influence drug efficacy could facilitate the development of more…

Chemical Exploration of a Highly Selective Scaffold with Activity against Intracellular .

Date Published: June 29, 2022
We previously identified a phenylthiourea series with activity against intracellular Mycobacterium tuberculosis using a high-throughput, high-content assay. We conducted a catalog structure-activity relationship study with a collection of 35 analogs. We identified several thiourea derivatives with excellent potency against intracellular bacteria and good selectivity over eukaryotic cells. Compounds had much…

A tRNA-Acetylating Toxin and Detoxifying Enzyme in Mycobacterium tuberculosis.

Date Published: June 29, 2022
Toxin-antitoxin (TA) systems allow bacteria to adapt to changing environments without altering gene expression. Despite being overrepresented in Mycobacterium tuberculosis, their physiological roles remain elusive. We describe a TA system in M. tuberculosis which we named TacAT due to its homology to previously discovered systems in Salmonella. The toxin, TacT,…

GSK2556286 Is a Novel Antitubercular Drug Candidate Effective with the Potential To Shorten Tuberculosis Treatment.

Date Published: June 21, 2022
As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC] = 0.07 μM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance…

Drug development challenges in nontuberculous mycobacterial lung disease: TB to the rescue.

Date Published: June 6, 2022
Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated with multiple repurposed drugs. Chemotherapy is long and often toxic, includes parenteral drugs, and suffers from poor cure rates. There is an urgent need for more efficacious, tolerated, and oral antibiotics optimized towards the treatment of NTM-PD, adapted to the spectrum of disease.