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1.
Antimicrob Agents Chemother ; 66(6): e0013222, 2022 06 21.
Article in English | MEDLINE | ID: mdl-35607978

ABSTRACT

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 [IC50] = 0.07 µM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs. In addition, it has shown efficacy in different mouse models of tuberculosis (TB) and has an adequate safety profile in two preclinical species. These features indicate a compound with a novel mode of action, although still not fully defined, that is effective against both multidrug-resistant (MDR) or extensively drug-resistant (XDR) and drug-sensitive (DS) M. tuberculosis with the potential to shorten the duration of treatment in novel combination drug regimens. (This study has been registered at ClinicalTrials.gov under identifier NCT04472897).


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Tuberculosis , Animals , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Macrophages , Mice , Microbial Sensitivity Tests , Tuberculosis/drug therapy , Tuberculosis, Multidrug-Resistant/drug therapy
4.
J Med Chem ; 60(16): 6880-6896, 2017 08 24.
Article in English | MEDLINE | ID: mdl-28806082

ABSTRACT

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.


Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimalarials/pharmacology , Oxadiazoles/pharmacology , 2,2'-Dipyridyl/administration & dosage , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacology , 2,2'-Dipyridyl/toxicity , Animals , Antimalarials/administration & dosage , Antimalarials/chemical synthesis , Antimalarials/toxicity , Atovaquone/pharmacology , Chloroquine/pharmacology , Drug Design , Female , Humans , Hydrazines/metabolism , Mice , Mutagenicity Tests , Mutagens/metabolism , Oxadiazoles/administration & dosage , Oxadiazoles/chemical synthesis , Oxadiazoles/toxicity , Parasitemia/drug therapy , Plasmodium falciparum/drug effects , Pyrimethamine/pharmacology , Structure-Activity Relationship
5.
Nat Commun ; 7: 12581, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27581223

ABSTRACT

Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis ß-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related ß-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.


Subject(s)
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/genetics , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/genetics , Indazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Sulfonamides/pharmacology , Tuberculosis, Pulmonary/drug therapy , Animals , Drug Resistance, Bacterial/genetics , Female , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Polymorphism, Single Nucleotide/genetics , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/prevention & control
6.
Nat Microbiol ; 1: 15006, 2016 Jan 18.
Article in English | MEDLINE | ID: mdl-27571973

ABSTRACT

Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/metabolism , Fatty Acid-Binding Proteins/metabolism , Fatty Acids, Essential/metabolism , Genes, Essential , Mycobacterium tuberculosis/metabolism , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Bacterial Proteins/genetics , Disease Models, Animal , Fatty Acid-Binding Proteins/genetics , Mice , Microbial Sensitivity Tests , Mutation, Missense , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/genetics , Point Mutation , Protein Binding , Protein Interaction Mapping , Tuberculosis/microbiology , Tuberculosis/pathology , Two-Hybrid System Techniques
8.
PLoS One ; 10(12): e0142293, 2015.
Article in English | MEDLINE | ID: mdl-26642067

ABSTRACT

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Algorithms , Cell Line, Tumor , Computational Biology/methods , Drug Design , Drug Discovery/methods , Hep G2 Cells , Humans
9.
ACS Infect Dis ; 1(12): 580-5, 2015 Dec 11.
Article in English | MEDLINE | ID: mdl-27623055

ABSTRACT

Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival.

10.
ACS Med Chem Lett ; 5(6): 657-61, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24944739

ABSTRACT

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 µM are able to show in vivo activity.

11.
PLoS One ; 8(4): e60933, 2013.
Article in English | MEDLINE | ID: mdl-23613759

ABSTRACT

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Mycobacterium tuberculosis/drug effects , Pyrazoles/pharmacology , Spiro Compounds/pharmacology , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/therapeutic use , Bacterial Proteins/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Chromatography, Thin Layer , Cord Factors , Disease Models, Animal , Dogs , Drug Resistance, Bacterial , Genotype , Hep G2 Cells , Humans , Kinetics , Mice , Microbial Sensitivity Tests , Microbial Viability/drug effects , Mutation/genetics , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/isolation & purification , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Treatment Outcome , Tuberculosis/drug therapy , Tuberculosis/microbiology
12.
ChemMedChem ; 8(2): 313-21, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23307663

ABSTRACT

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Drug Discovery/methods , Mycobacterium bovis/drug effects , Mycobacterium tuberculosis/drug effects , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Databases, Pharmaceutical , Hep G2 Cells , High-Throughput Screening Assays , Humans , Microbial Sensitivity Tests , Tuberculosis/drug therapy
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