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1.
Proc Natl Acad Sci U S A ; 121(2): e2314101120, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38165935

RESUMO

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.


Assuntos
Anti-Infecciosos , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Humanos , Animais , Camundongos , Espectinomicina/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antibacterianos/farmacologia , Micobactérias não Tuberculosas , Anti-Infecciosos/farmacologia , Etilenos/farmacologia , Testes de Sensibilidade Microbiana
2.
Antimicrob Agents Chemother ; : e0071624, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39345140

RESUMO

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

3.
Mol Pharmacol ; 102(3): 172-182, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35798366

RESUMO

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action. SIGNIFICANCE STATEMENT: Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.


Assuntos
Antimaláricos , Antagonistas do Ácido Fólico , Animais , Ânions/química , Ânions/metabolismo , Antimaláricos/farmacologia , Eritrócitos/metabolismo , Humanos , Nutrientes , Plasmodium falciparum/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-29483122

RESUMO

Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to that of spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Chlamydia/tratamento farmacológico , Chlamydia trachomatis/efeitos dos fármacos , Gonorreia/tratamento farmacológico , Neisseria gonorrhoeae/efeitos dos fármacos , Doenças Bacterianas Sexualmente Transmissíveis/tratamento farmacológico , Espectinomicina/análogos & derivados , Espectinomicina/uso terapêutico , Animais , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Infecções por Chlamydia/microbiologia , Coinfecção/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Feminino , Gentamicinas/uso terapêutico , Gonorreia/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Subunidades Ribossômicas Menores de Bactérias/efeitos dos fármacos
5.
bioRxiv ; 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38798577

RESUMO

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

6.
J Antibiot (Tokyo) ; 72(9): 693-701, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31164713

RESUMO

New antibiotics that are active against multi-drug-resistant strains and difficult-to-treat bacterial infections are needed. Synthetic modification of spectinomycin, a bacterial protein synthesis inhibitor, has been shown to increase antibacterial activity compared with spectinomycin. Aminomethyl spectinomycins are active against Gram-negative and Gram-positive bacterial pathogens. In this study, the ability of aminomethyl spectinomycins to treat biothreat pathogens is examined by MIC profiling, synergy testing, and in vivo efficacy experiments. Compound 1950 exhibited potent antibacterial activity against Gram-negative pathogens Brucella spp., Burkholderia mallei, and Francisella tularensis, but showed little to no growth inhibition against Burkholderia pseudomallei, Bacillus anthracis, and Yersinia pestis. Combination testing in checkerboard assays revealed that aminomethyl spectinomycin-antibiotic combinations had mainly an additive effect against the susceptible biodefense pathogens. The in vivo efficacy of compound 1950 was also demonstrated in mice infected with B. mallei (FMH) or F. tularensis (SchuS4). These results suggest that aminomethyl spectinomycins are promising new candidates for development of therapeutics against biodefense bacterial agents.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Espectinomicina/análogos & derivados , Espectinomicina/farmacologia , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Modelos Animais de Doenças , Interações Medicamentosas , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Espectinomicina/química , Espectinomicina/uso terapêutico , Resultado do Tratamento
7.
ACS Infect Dis ; 3(1): 72-88, 2017 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-28081607

RESUMO

Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure-activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure-activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class.


Assuntos
Antituberculosos/farmacologia , Ribossomos/efeitos dos fármacos , Espectinomicina/análogos & derivados , Espectinomicina/farmacologia , Antituberculosos/química , Descoberta de Drogas , Modelos Moleculares , Estrutura Molecular , Espectinomicina/química , Relação Estrutura-Atividade
9.
Sci Transl Med ; 7(288): 288ra75, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25995221

RESUMO

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Descoberta de Drogas , Farmacorresistência Bacteriana , Infecções Respiratórias/tratamento farmacológico , Doenças Bacterianas Sexualmente Transmissíveis/tratamento farmacológico , Espectinomicina/farmacologia , Animais , Antibacterianos/efeitos adversos , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Bactérias/metabolismo , Bactérias/patogenicidade , Proteínas de Bactérias/biossíntese , Chlorocebus aethiops , Simulação por Computador , Desenho Assistido por Computador , Modelos Animais de Doenças , Interações Medicamentosas , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Doenças Bacterianas Sexualmente Transmissíveis/diagnóstico , Doenças Bacterianas Sexualmente Transmissíveis/microbiologia , Espectinomicina/efeitos adversos , Espectinomicina/análogos & derivados , Espectinomicina/síntese química , Espectinomicina/farmacocinética , Relação Estrutura-Atividade , Células Vero
10.
Nat Med ; 20(2): 152-158, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24464186

RESUMO

Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Desenho de Fármacos , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Espectinomicina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Transportadores de Cassetes de Ligação de ATP/metabolismo , Amidas/síntese química , Amidas/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Camundongos , Ribossomos/efeitos dos fármacos , Espectinomicina/química , Relação Estrutura-Atividade
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