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1.
Proc Natl Acad Sci U S A ; 113(31): E4523-30, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27432954

RESUMO

The rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms. Mycobacterium tuberculosis (Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains of rv2887, a gene encoding a transcriptional repressor of the MarR family. The mutations in Rv2887 led to markedly increased expression of rv0560c. We characterized Rv0560c as an S-adenosyl-L-methionine-dependent methyltransferase that N-methylates 14, abolishing its mycobactericidal activity. An Mtb strain lacking rv0560c became resistant to 14 by mutating decaprenylphosphoryl-ß-d-ribose 2-oxidase (DprE1), an essential enzyme in arabinogalactan synthesis; 14 proved to be a nanomolar inhibitor of DprE1, and methylation of 14 by Rv0560c abrogated this activity. Thus, 14 joins a growing list of DprE1 inhibitors that are potently mycobactericidal. Bacterial methylation of an antibacterial agent, 14, catalyzed by Rv0560c of Mtb, is a previously unreported mechanism of AMR.


Assuntos
Antituberculosos/metabolismo , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana , Mycobacterium tuberculosis/metabolismo , Antituberculosos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Benzimidazóis/química , Benzimidazóis/metabolismo , Regulação Bacteriana da Expressão Gênica , Metilação , Metiltransferases/química , Metiltransferases/genética , Metiltransferases/metabolismo , Modelos Moleculares , Estrutura Molecular , Mutação , Mycobacterium tuberculosis/genética , Domínios Proteicos , Proteínas Repressoras/química , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , S-Adenosilmetionina/metabolismo
2.
Sci Transl Med ; 14(643): eaaz6280, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35507672

RESUMO

The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.


Assuntos
Mycobacterium tuberculosis , Pró-Fármacos , Tuberculose , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Etionamida/química , Etionamida/farmacologia , Etionamida/uso terapêutico , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Tuberculose/tratamento farmacológico
3.
ACS Infect Dis ; 8(3): 557-573, 2022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35192346

RESUMO

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.


Assuntos
COVID-19 , Mycobacterium tuberculosis , Animais , Indústria Farmacêutica , Camundongos , SARS-CoV-2 , Universidades , beta-Lactamas/farmacologia
4.
J Med Chem ; 63(9): 4732-4748, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32275415

RESUMO

Screening of a GSK-proprietary library against intracellular Mycobacterium tuberculosis identified 1, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Benzoxazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxigenases/metabolismo , Pró-Fármacos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/metabolismo , Benzoxazóis/síntese química , Benzoxazóis/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Relação Estrutura-Atividade
5.
Sci Adv ; 5(3): eaav2104, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30906866

RESUMO

The stringent response enables Mycobacterium tuberculosis (Mtb) to shut down its replication and metabolism under various stresses. Here we show that Mtb lacking the stringent response enzyme RelMtb was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved relMtb -deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of relMtb increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of RelMtb and showed that the lead compound X9 was able to directly kill nutrient-starved M. tuberculosis and enhanced the killing activity of isoniazid. Inhibition of RelMtb is a promising approach to target M. tuberculosis persisters, with the potential to shorten the duration of TB treatment.


Assuntos
Proteínas de Bactérias/genética , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/genética , Animais , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Cristalografia por Raios X , Replicação do DNA/efeitos dos fármacos , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , GTP Pirofosfoquinase/antagonistas & inibidores , GTP Pirofosfoquinase/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Isoniazida/química , Isoniazida/farmacologia , Camundongos , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Conformação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/patologia
6.
ACS Infect Dis ; 5(8): 1433-1445, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31184461

RESUMO

The historical view of ß-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a ß-lactamase inhibitor. However, most antimycobacterial ß-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 ß-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3' that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a ß-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A ß-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent ß-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states.


Assuntos
Antituberculosos/farmacologia , Cefalosporinas/farmacologia , Replicação do DNA , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Tionas/farmacologia , Administração Oral , Animais , Antituberculosos/administração & dosagem , Callithrix , Cefalosporinas/administração & dosagem , Descoberta de Drogas , Feminino , Células Hep G2 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mycobacterium tuberculosis/fisiologia , Piridinas/administração & dosagem , Tionas/administração & dosagem
7.
J Med Chem ; 61(24): 11327-11340, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30457865

RESUMO

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Administração Intravenosa , Administração Oral , Animais , Antituberculosos/efeitos adversos , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/antagonistas & inibidores , Feminino , Coração/efeitos dos fármacos , Humanos , Dose Máxima Tolerável , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Coelhos
8.
ACS Infect Dis ; 1(12): 580-5, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-27623055

RESUMO

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.

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