RESUMO
Ever since the first ß-lactam antibiotic, penicillin, was introduced into the clinic over 70 years ago, resistance has been observed because of the presence of ß-lactamase enzymes, which hydrolyze the ß-lactam ring of ß-lactam antibiotics. Early ß-lactamase enzymes were all of the serine ß-lactamase (SBL) type, but more recently, highly resistant Gram-negative strains have emerged in which metallo-ß-lactamase (MBL) enzymes are responsible for resistance. The two types of ß-lactamase enzymes are structurally and mechanistically different but serve the same purpose in bacteria. The SBLs use an active serine group as a nucleophile to attack the ß-lactamase ring, forming a covalent intermediate that is subsequently hydrolyzed. In contrast, the MBLs use a zinc ion to activate the ß-lactam toward nucleophilic attack by a hydroxide anion held between two zinc ions. In this Account, we review our recent contribution to the field of ß-lactamase inhibitor design in terms of both SBL and MBL inhibitors. We describe how we have approached these challenges from the particular perspective of a small biotechnology company, identifying new inhibitors when faced with either a paucity of starting points for medicinal chemistry (MBL inhibitors) or else an abundance of prior research necessitating a search for novelty, improvement, and differentiation (SBL inhibitors). During the journey from the beginning of lead optimization to successful identification of a preclinical candidate for development, we encountered and solved a range of issues. For example, in the MBL inhibitor series we were able to prevent metabolic cleavage of a glycinamide moiety by circulating amidases while still retaining the activity by converting the amino group into a guanidine. In the SBL inhibitor series, the structure-activity relationship led us to consider introducing a fluorine substituent adjacent to a urea functionality. At first sight this grouping would appear to be chemically unstable. However, deeper theoretical considerations suggested that this would not be the case, and in practice the compound is remarkably stable. Both examples serve to illustrate the importance of scientific insight and the necessity to explore speculative hypotheses as part of the creative medicinal chemistry process.
Assuntos
Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Desenho de Fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/químicaRESUMO
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of ß-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine ß-lactamases (SBLs; e.g., KPC-2 and OXA-48) and metallo-ß-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of ß-lactam antibiotics with ß-lactamase inhibitors are active only against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of meropenem (MEM) against a broad range of MBL-producing CRE and restore its efficacy against an Escherichia coli NDM-1-producing strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor-carbapenem combination. This would complement the existing weaponry against CRE and address an important and growing unmet medical need.
Assuntos
Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/genéticaRESUMO
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Assuntos
Antibacterianos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Técnicas de Química Sintética , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/metabolismo , Bactérias Anaeróbias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Infecções Pneumocócicas/tratamento farmacológico , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzamidas/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Desenho de Fármacos , Oxazóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Benzamidas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/química , Staphylococcus aureus/química , Relação Estrutura-AtividadeRESUMO
A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.
Assuntos
Antibacterianos/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , DNA Bacteriano/química , DNA Bacteriano/efeitos dos fármacos , DNA Super-Helicoidal/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Álcoois/química , Antibacterianos/síntese química , Antibacterianos/química , Benzotiazóis/síntese química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus , Relação Estrutura-AtividadeRESUMO
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
Assuntos
Bactérias/enzimologia , Naftiridinas/química , Naftiridinas/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Cristalografia por Raios X , Cães , Ativação Enzimática/efeitos dos fármacos , Haplorrinos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , RatosRESUMO
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , Desenho de Fármacos , Ácidos Isonipecóticos/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Benzotiazóis/síntese química , DNA Girase/química , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/enzimologia , Ativação Enzimática/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/enzimologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
LasB elastase is a broad-spectrum exoprotease and a key virulence factor of Pseudomonas aeruginosa, a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1ß. Furthermore, inhibition of LasB-mediated IL-1ß activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in P. aeruginosa infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen.
Assuntos
Pseudomonas aeruginosa , Fatores de Virulência , Animais , Camundongos , Cinética , Modelos Animais , Elastase PancreáticaRESUMO
As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.
Assuntos
Amidas/química , Antibacterianos/química , Antibacterianos/farmacologia , DNA Topoisomerases Tipo II/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores da Topoisomerase II/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Antibacterianos/síntese química , Sítios de Ligação , Simulação por Computador , DNA Topoisomerases Tipo II/metabolismo , Cães , Haplorrinos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , DNA Topoisomerases Tipo II/química , Dioxanos/química , Dioxanos/farmacologia , Naftiridinas/química , Naftiridinas/farmacologia , Piperidinas/química , Inibidores da Topoisomerase II/química , Animais , Antibacterianos/uso terapêutico , DNA Topoisomerases Tipo II/metabolismo , Dioxanos/uso terapêutico , Modelos Animais de Doenças , Cães , Haplorrinos , Humanos , Pneumopatias/tratamento farmacológico , Testes de Sensibilidade Microbiana , Naftiridinas/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêuticoRESUMO
The cis-hydrindane motif is found in a number of natural products that display important biological activity. A flexible, stereoselective approach to the framework has been developed that features highly diastereoselective, SmI(2)-mediated cyclisations. The strategy has been exploited in the first synthesis of the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural product, pleuromutilin.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Indanos/química , Samário/química , Produtos Biológicos/química , Ciclização , Diterpenos/síntese química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Compostos Policíclicos , Estereoisomerismo , PleuromutilinasRESUMO
Why is P. aeruginosa LasB elastase an attractive target for antivirulence therapy and what is the state-of-the art in LasB inhibitor design and development?
Assuntos
Antibacterianos/uso terapêutico , Proteínas de Bactérias/antagonistas & inibidores , Metaloendopeptidases/antagonistas & inibidores , Elastase Pancreática/antagonistas & inibidores , Infecções por Pseudomonas/tratamento farmacológico , Animais , Proteínas de Bactérias/metabolismo , Desenvolvimento de Medicamentos , Humanos , Metaloendopeptidases/metabolismo , Elastase Pancreática/metabolismo , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/patogenicidade , VirulênciaRESUMO
Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (K i = 0.16 µM and 0.12 µM, respectively).
RESUMO
The clinical effectiveness of the important ß-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-ß-lactamase (MBL) enzymes. To address this resistance issue, multiple ß-lactam/ß-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.
Assuntos
Enterobacteriaceae , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Meropeném/farmacologia , Monobactamas , Inibidores de beta-Lactamases/farmacologiaRESUMO
The diazabicyclooctanes (DBOs) are a class of serine ß-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of ß-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of ß-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.
Assuntos
Acinetobacter/efeitos dos fármacos , Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Octanos/química , beta-Lactamases/química , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Sítios de Ligação , Carbapenêmicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Octanos/metabolismo , Octanos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismoRESUMO
The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new ß-lactamase inhibitors to be used in conjunction with carbapenems and other ß-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-ß-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.
Assuntos
Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Infecções por Enterobacteriaceae/tratamento farmacológico , Inibidores de beta-Lactamases/química , Carbapenêmicos/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/farmacologia , beta-LactamasesRESUMO
3(2H)-Furanones can be prepared by a catalytic asymmetric protocol from enynones, which, if electron-rich, require only one reagent and involve two reactions in a single operation--a domino process.
Assuntos
Furanos/química , Alcinos/química , Catálise , Furanos/síntese química , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy.