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1.
Antimicrob Agents Chemother ; 67(9): e0038123, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37493373

RESUMO

Necrotic lesions and cavities filled with caseum are a hallmark of mycobacterial pulmonary disease. Bronchocavitary Mycobacterium abscessus disease is associated with poor treatment outcomes. In caseum surrogate, M. abscessus entered an extended stationary phase showing tolerance to killing by most current antibiotics, suggesting that caseum persisters contribute to the poor performance of available treatments. Novel ADP-ribosylation-resistant rifabutin analogs exhibited bactericidal activity against these M. abscessus persisters at concentrations achievable by rifamycins in caseum.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Rifamicinas , Humanos , Rifabutina/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana
2.
Artigo em Inglês | MEDLINE | ID: mdl-33558292

RESUMO

Global infections by non-tuberculous mycobacteria (NTM) are steadily rising. New drugs are needed to treat NTM infections, but the NTM drug pipeline remains poorly populated and focused on repurposing or reformulating approved antibiotics. We sought to accelerate de novo NTM drug discovery by testing advanced compounds with established activity against Mycobacterium tuberculosis 3-aminomethyl 4-halogen benzoxaboroles, a novel class of leucyl-tRNA synthetase inhibitors, were recently discovered as active against M. tuberculosis Here, we report that the benzoxaborole EC/11770 is not only a potent anti-tubercular agent but is active against the M. abscessus and M. avium complexes. Focusing on M. abscessus, which causes the most difficult-to-cure NTM disease, we show that EC/11770 retained potency against drug-tolerant biofilms in vitro and was effective in a mouse lung infection model. Resistant mutant selection experiments showed a low frequency of resistance and confirmed leucyl-tRNA synthetase as the target. This work establishes the benzoxaborole EC/11770 as a novel preclinical candidate for the treatment of NTM lung disease and tuberculosis and validates leucyl-tRNA synthetase as an attractive target for the development of broad-spectrum anti-mycobacterials.

3.
Antimicrob Agents Chemother ; 67(2): e0145922, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36688684

RESUMO

The combination of the ß-lactam tebipenem and the ß-lactamase inhibitor avibactam shows potent bactericidal activity against Mycobacterium abscessus in vitro. Here, we report that the combination of the respective oral prodrugs tebipenem-pivoxil and avibactam ARX-1796 showed efficacy in a mouse model of M. abscessus lung infection. The results suggest that tebipenem-avibactam presents an attractive oral drug candidate pair for the treatment of M. abscessus pulmonary disease and could inform the design of clinical trials.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Modelos Animais de Doenças , Pulmão , Testes de Sensibilidade Microbiana
4.
Molecules ; 27(20)2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36296540

RESUMO

Unlike Tuberculosis (TB), Mycobacterium abscessus lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo M. abscessus drug discovery is urgently needed but is hampered by the bacterium's extreme drug resistance profile, leaving the current drug pipeline underpopulated. One proposed strategy to accelerate de novo M. abscessus drug discovery is to prioritize screening of advanced TB-active compounds for anti-M. abscessus activity. This approach would take advantage of the greater chance of homologous drug targets between mycobacterial species, increasing hit rates. Furthermore, the screening of compound series with established structure-activity-relationship, pharmacokinetic, and tolerability properties should fast-track the development of in vitro anti-M. abscessus hits into lead compounds with in vivo efficacy. In this review, we evaluated the effectiveness of this strategy by examining the literature. We found several examples where the screening of advanced TB chemical matter resulted in the identification of anti-M. abscessus compounds with in vivo proof-of-concept, effectively populating the M. abscessus drug pipeline with promising new candidates. These reports validate the screening of advanced TB chemical matter as an effective means of fast-tracking M. abscessus drug discovery.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Mycobacterium , Tuberculose , Humanos , Descoberta de Drogas , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana
5.
Angew Chem Int Ed Engl ; 61(45): e202211498, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36222275

RESUMO

Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structure-based approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.


Assuntos
Mycobacterium , Rifamicinas , Antibacterianos/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana , Rifamicinas/farmacologia , Rifamicinas/química , ADP-Ribosilação
6.
Antimicrob Agents Chemother ; 65(10): e0115621, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34280020

RESUMO

Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. We recently reported that the antitubercular 4-halogenated benzoxaboroles are active against Mycobacterium abscessus. Here, we find that the nonhalogenated benzoxaborole epetraborole, a clinical candidate developed for Gram-negative infections, is also active against M. abscessus in vitro and in a mouse model of infection. This expands the repertoire of advanced lead compounds for the discovery of a benzoxaborole-based candidate to treat M. abscessus lung disease.


Assuntos
Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antituberculosos , Pneumopatias/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas
7.
Antimicrob Agents Chemother ; 65(9): e0097821, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34228543

RESUMO

Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat Mycobacterium abscessus infections due to poor in vitro activity. While rifabutin, another rifamycin, has better anti-M. abscessus activity, its activity is far from the nanomolar potencies of rifamycins against Mycobacterium tuberculosis. Here, we asked (i) why is rifabutin more active against M. abscessus than rifampicin, and (ii) why is rifabutin's anti-M. abscessus activity poorer than its anti-TB activity? Comparative analysis of naphthoquinone- versus naphthohydroquinone-containing rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase ArrMab like rifampicin, preventing it from achieving the nanomolar activity that it displays against M. tuberculosis. Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that rifamycins more potent than rifabutin should contain the molecule's naphthoquinone core plus a modification that blocks ADP-ribosylation at its C-23. To test these predictions, we performed a blinded screen of a diverse collection of 189 rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively resistant naphthoquinone core and C-25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to rifamycins and provides proof of concept for the repositioning of rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.


Assuntos
Mycobacterium abscessus , Rifamicinas , ADP-Ribosilação , Testes de Sensibilidade Microbiana , Rifabutina/farmacologia , Rifamicinas/farmacologia
8.
Antimicrob Agents Chemother ; 65(12): e0151421, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34606340

RESUMO

Fluoroquinolones-the only clinically used DNA gyrase inhibitors-are effective against tuberculosis (TB) but are in limited clinical use for nontuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis gyrase inhibitors (MGIs), a subclass of novel bacterial topoisomerase inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus. Here, we show that the MGI EC/11716 not only has potent anti-tubercular activity but is active against M. abscessus and M. avium in vitro. Focusing on M. abscessus, which causes the most difficult to cure NTM disease, we show that EC/11716 is bactericidal, active against drug-tolerant biofilms, and efficacious in a murine model of M. abscessus lung infection. Based on resistant mutant selection experiments, we report a low frequency of resistance to EC/11716 and confirm DNA gyrase as its target. Our findings demonstrate the potential of NBTIs as anti-M. abscessus and possibly broad-spectrum anti-mycobacterial agents.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Mycobacterium tuberculosis , Animais , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas , Tioinosina/análogos & derivados , Inibidores da Topoisomerase II/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-31964791

RESUMO

Lung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation. Recent medicinal chemistry campaigns resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ which are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, a clinical development candidate of this series, shows attractive in vitro antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 is active against M. abscessus TBAJ-876 displayed submicromolar in vitro activity against reference strains representing the three subspecies of M. abscessus and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti-M. abscessus antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be coadministered with currently used drugs. Efficacy studies, employing a mouse model of M. abscessus infection, demonstrated potent activity in vivo In summary, we demonstrate that TBAJ-876 shows attractive in vitro and in vivo activities against M. abscessus, similar to its BDQ parent. This suggests that next-generation BDQ, with improved tolerability and pharmacological profiles, may be useful for the treatment of M. abscessus lung disease in addition to the treatment of tuberculosis.


Assuntos
Antibacterianos/farmacologia , Diarilquinolinas/farmacologia , Mycobacterium abscessus/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos SCID , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium abscessus/isolamento & purificação
10.
Antibiotics (Basel) ; 13(5)2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38786132

RESUMO

This study investigates the in vitro activity of Nα-aroyl-N-aryl-phenylalanine amides (AAPs), previously identified as antimycobacterial RNA polymerase (RNAP) inhibitors, against a panel of 25 non-tuberculous mycobacteria (NTM). The compounds, including the hit compound MMV688845, were selected based on their structural diversity and previously described activity against mycobacteria. Bacterial strains, including the M. abscessus complex, M. avium complex, and other clinically relevant NTM, were cultured and subjected to growth inhibition assays. The results demonstrate significant activity against the most common NTM pathogens from the M. abscessus and M. avium complexes. Variations in activity were observed against other NTM species, with for instance M. ulcerans displaying high susceptibility and M. xenopi and M. simiae resistance to AAPs. Comparative analysis of RNAP ß and ß' subunits across mycobacterial species revealed strain-specific polymorphisms, providing insights into differential compound susceptibility. While conservation of target structures was observed, differences in compound activity suggested influences beyond drug-target interactions. This study highlights the potential of AAPs as effective antimycobacterial agents and emphasizes the complex interplay between compound structure, bacterial genetics, and in vitro activity.

11.
ChemMedChem ; 19(6): e202300593, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38329388

RESUMO

Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 novel AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma-stable and non-cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.


Assuntos
Antibacterianos , Mycobacterium tuberculosis , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Amidas/farmacologia
12.
Microbiol Spectr ; : e0190023, 2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37681986

RESUMO

The clinical utility of rifamycins against non-tuberculous mycobacterial (NTM) disease is limited by intrinsic drug resistance achieved by ADP-ribosyltransferase Arr. By blocking the site of ribosylation, we recently optimized a series of analogs with substantially improved potency against Mycobacterium abscessus. Here, we show that a representative member of this series is significantly more potent than rifabutin against major NTM pathogens expressing Arr, providing a powerful medicinal chemistry approach to expand the antimycobacterial spectrum of rifamycins. IMPORTANCE Lung disease caused by a range of different species of non-tuberculous mycobacteria (NTM) is difficult to cure. The rifamycins are very active against Mycobacterium tuberculosis, which causes tuberculosis (TB), but inactive against many NTM species. Previously, we showed that the natural resistance of the NTM Mycobacterium abscessus to rifamycins is due to enzymatic inactivation of the drug by the bacterium. We generated chemically modified versions of rifamycins that prevent inactivation by the bacterium and thus become highly active against M. abscessus. Here, we show that such a chemically modified rifamycin is also highly active against several additional NTM species that harbor the rifamycin inactivating enzyme found in M. abscessus, including M. chelonae, M. fortuitum, and M. simiae. This finding expands the potential therapeutic utility of our novel rifamycins to include several currently difficult-to-cure NTM lung disease pathogens beyond M. abscessus.

13.
J Med Chem ; 66(7): 5079-5098, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-37001025

RESUMO

Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2R)-N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC90 6.25-12.5 µM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential R configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against M. abscessus, Mycobacterium intracellulare, Mycobacterium smegmatis, and Mycobacterium tuberculosis. The sulfone derivatives exhibit lower MIC90 values (M. abscessus: 0.78 µM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of M. abscessus at 12.5 µM), while they are not cytotoxic against mammalian cell lines.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Mycobacterium tuberculosis , Animais , Amidas , Antibacterianos/farmacologia , Antibacterianos/química , Mamíferos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/microbiologia
14.
Microbiol Spectr ; 10(6): e0276022, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36377951

RESUMO

In a library screen of tuberculosis-active compounds for anti-Mycobacterium abscessus activity, we previously identified the synthetic phenylalanine amide MMV688845. In Mycobacterium tuberculosis, this class was shown to target the RpoB subunit of RNA polymerase, engaging a binding site distinct from that of the rifamycins. Due to its bactericidal activity, rifampicin is a key drug for the treatment of tuberculosis (TB). However, this natural product shows poor potency against M. abscessus due to enzymatic modification, and its clinical use is limited. Here, we carried out in vitro microbiological profiling of MMV688845 to determine its attractiveness as a substrate for a chemistry optimization project. MMV688845 was broadly active against the M. abscessus complex, displayed bactericidal against M. abscessus in vitro, and in a macrophage infection model showed additivity with commonly used anti-M. abscessus antibiotics and synergy with macrolides. Analyses of spontaneous resistant mutants mapped resistance to RpoB, confirming that MMV688845 has retained its target in M. abscessus. Together with its chemical tractability, the presented microbiological profiling reveals MMV688845 as an attractive starting point for hit-to-lead development to improve potency and to identify a lead compound with demonstrated oral in vivo efficacy. IMPORTANCE Infections with nontuberculous mycobacteria are an increasing health problem, and only a few new drug classes show activity against these multidrug-resistant bacteria. Due to insufficient therapy options, the development of new drug leads is necessary and should be advanced. The lead compound MMV688845, a substance active against M. abscessus complex, was characterized in depth. In various assays, it showed activity against M. abscessus, synergy with other antibiotics, and bactericidal effects.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Mycobacterium tuberculosis , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Rifampina/farmacologia , Rifampina/uso terapêutico , Testes de Sensibilidade Microbiana
15.
Expert Opin Drug Discov ; 14(9): 867-878, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31195849

RESUMO

Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.


Assuntos
Antibacterianos/administração & dosagem , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Rifamicinas/administração & dosagem , Animais , Reposicionamento de Medicamentos , Humanos , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Mycobacterium abscessus/isolamento & purificação , Rifabutina/administração & dosagem , Rifampina/administração & dosagem
16.
ACS Infect Dis ; 4(6): 918-925, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29708735

RESUMO

The study of the bacterial periplasm requires techniques with sufficient spatial resolution and sensitivity to resolve the components and processes within this subcellular compartment. Peroxidase-mediated biotinylation has enabled targeted labeling of proteins within subcellular compartments of mammalian cells. We investigated whether this methodology could be applied to the bacterial periplasm. In this study, we demonstrated that peroxidase-mediated biotinylation can be performed in mycobacteria and Escherichia coli. To eliminate detection artifacts from natively biotinylated mycobacterial proteins, we validated two alternative labeling substrates, tyramide azide and tyramide alkyne, which enable biotin-independent detection of labeled proteins. We also targeted peroxidase expression to the periplasm, resulting in compartment-specific labeling of periplasmic versus cytoplasmic proteins in mycobacteria. Finally, we showed that this method can be used to validate protein relocalization to the cytoplasm upon removal of a secretion signal. This novel application of peroxidase-mediated protein labeling will advance efforts to characterize the role of the periplasm in bacterial physiology and pathogenesis.


Assuntos
Proteínas de Bactérias/química , Biotina , Proteínas Periplásmicas/química , Peroxidase , Coloração e Rotulagem , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biotina/química , Biotinilação , Química Click , Citoplasma , Escherichia coli/metabolismo , Proteínas Periplásmicas/genética , Proteínas Periplásmicas/metabolismo , Peroxidase/química , Peroxidase/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo
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