Multidrug-resistant tuberculosis: household transmission and associated risk factors

Given the global burden of tuberculosis, and more precisely of multidrug-resistant (MDR) tuberculosis (TB), one of the most pressing epidemiological issues is the study and prevention of transmission. The study aims to assess transmission within households that present at least two cases of MDR-TB and the possible risk factors, from MDR-TB isolates collected in Lima, Peru and further characterized by genotyping methods, spoligotyping and mycobacterial interspersed repetitive units (MIRU) - variable number tandem repeat (VNTR), used for DNA fingerprinting. Apart from the genotyping results, the data set also provides the drug susceptibility testing (DST) profile for each isolate, as well as information on the households and the patients. The key assumption to transform molecular data into epidemiological data is that all identical isolates are classified in the same cluster, the cluster belong to a unique strain of tuberculosis, and a unique strain infecting more than one individual is presumed to be the result of direct transmission. The analysis is divided in two parts, first the establishment of household transmission or outside transmission for each isolate and then the following epidemiological analysis; and requires the use of Matlab and Stata software. The main results are the cohort characteristics, the concordance between the two genotyping methods, the clusters' composition and size frequency, the transmission analysis, the amplification of resistance analysis and the risk factors analysis for household transmission. From there, the main findings are the high rate of household transmission (more than 80%) of the isolates and drug resistance amplification (up to 10 new resisitances within one household clustered strain). The risk factor analysis did not present any significant results, but a few trends that are worth to explore in the future

New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis

Andrej Benjak, Stewart Cole, Shi-Yan Caroline Foo, Andréanne Lupien, Jérémie Piton, Anthony Vocat

The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of action of new, potent quinazoline derivatives was investigated against Mycobacterium tuberculosis (M. tb). Four derivatives 11626141, 11626142, 11626252 and 11726148 showed good activity (MIC ranging from 0.02-0.09 mu g/mL) and low toxicity (TD50 >= 5 mu g/mL) in vitro against M. tb strain H37Rv and HepG2 cells, respectively. 11626252 was the most selective compound from this series. Quinazoline derivatives were found to target cytochrome bc(1) by whole-genome sequencing of mutants selected with 11626142. Two resistant mutants harboured the transversion T943G (Trp312Gly) and the transition G523A (Gly175Ser) in the cytochrome bc(1) complex cytochrome b subunit (QcrB). Interestingly, a third mutant QuinR-M1 contained a mutation in the Rieske iron-sulphur protein (QcrA) leading to resistance to quinazoline and other QcrB inhibitors, the first report of cross-resistance involving QcrA. Modelling of both QcrA and QcrB revealed that all three resistance mutations are located in the stigmatellin pocket, as previously observed for other QcrB inhibitors such as Q203, AX-35, and lansoprazole sulfide (LPZs). Further analysis of the mode of action in vitro revealed that 11626252 exposure leads to ATP depletion, a decrease in the oxygen consumption rate and also overexpression of the cytochrome bd oxidase in M. tb. Our findings suggest that quinazoline-derived compounds are a new and attractive chemical entity for M. tb drug development targeting two separate subunits of the cytochrome bc(1) complex.

2020

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Stewart Cole, Benoit Lechartier

Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O-2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis.

Amer Soc Microbiology2015

4-Pyrimidinylamino-benzenesulfonamide derivatives and their use for the inhibition of polo-like kinase 1 (PLK1) for the treatment of cancer and their use for the treatment of bacterial infections

Stewart Cole, Ruben Hartkoorn, Edina Rita Székely

The present invention relates to 4-pyrimidinylamino-benzenesulfonamide derivatives of general formula (I) and pharmaceutically acceptable salts, solvates, hydrates, regioisomeric and polymorphic forms thereof, processes for manufacturing of them, the use of them, as well as pharmaceutical compositions containing at least one of them as pharmaceutically active agent(s) together with pharmaceutically acceptable carrier, excipient and/or diluents, especially for the inhibition of polo-like kinases (PLKs) and the treatment of cancer. Said 4-pyrimidinylamino-benzenesulfonamide compounds have been also identified as new drug candidates for the prevention and/or treatment of infectious diseases like bacterial diseases e.g. tuberculosis, including the currently multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) as well as for preventing tuberculosis.

2015