bOver the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden.
Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action are DprE1 inhibitors targeting an essential process in cell wall synthesis of
Mycobacterium tuberculosis
. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169 and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology, and perform comprehensive analysis of plasma, lung and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after two months of treatment. Superior efficacy was observed for OPC-167832 even at low dose levels, which can be attributed to its low MIC, favorable distribution and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against
Mycobacterium tuberculosis
through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg
2+
-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones.
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.
Phenotypic
whole cell high-throughput screening of a ∼150,000
diverse set of compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as a moderately active hit. Structure–activity relationship
(SAR) studies demonstrated a clear scope to improve whole cell potency
to MIC values of <0.5 μM, and a plausible pharmacophore model
was developed to describe the chemical space of active compounds.
Compounds are bactericidal in vitro against replicating
Mtb and retained activity against multidrug-resistant clinical isolates.
Initial biology triage assays indicated cell wall biosynthesis as
a plausible mode-of-action for the series. However, no cross-resistance
with known cell wall targets such as MmpL3, DprE1, InhA, and EthA
was detected, suggesting a potentially novel mode-of-action or inhibition.
The in vitro and in vivo drug metabolism
and pharmacokinetics profiles of several active compounds from the
series were established leading to the identification of a compound
for in vivo efficacy proof-of-concept studies.
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