RESUMEN
Antimicrobial resistance (AMR) is a major global health threat estimated to have caused the deaths of 1.27 million people in 2019, which is more than HIV/AIDS and malaria deaths combined. AMR also has significant consequences on the global economy. If not properly addressed, AMR could immensely impact the world's economy, further increasing the poverty burden in low- and middle-income countries. To mitigate the risk of a post-antibiotic society, where the ability to effectively treat common bacterial infections is being severely threatened, it is necessary to establish a continuous supply of new and novel antibacterial medicines. However, there are gaps in the current pipeline that will prove difficult to address, given the time required to develop new agents. To understand the status of upstream antibiotic development and the challenges faced by drug developers in the early development stage, the World Health Organization has regularly assessed the preclinical and clinical antibacterial development pipeline. The review identifies potential new classes of antibiotics or novel mechanisms of action that can better address resistant bacterial strains. This proactive approach is necessary to stay ahead of evolving resistance patterns and to support the availability of effective treatment options. This review examines the trends in preclinical development and attempts to identify gaps and potential opportunities to overcome the numerous hurdles in the early stages of the antibacterial research and development space.
Asunto(s)
Antibacterianos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Humanos , Desarrollo de Medicamentos , Salud Global , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Farmacorresistencia Bacteriana , Animales , Evaluación Preclínica de Medicamentos , Organización Mundial de la SaludRESUMEN
BACKGROUND: Estimating the contribution of endplate oedema known as Modic changes to lower back pain (LBP) has been the subject of multiple observational studies and reviews, some of which conclude that the evidence for an association of Modic change with LBP is uncertain while others demonstrate a clear link. The clinical trials demonstrating the benefit of basivertebral nerve ablation, a therapeutic intervention, in a tightly defined homogenous patient group with chronic LBP and Modic changes type 1 or type 2, provides further evidence for the contribution of Modic changes to LBP and shows that in these subjects, nerve ablation substantially reduces pain and disability. These interventional studies provide direct evidence that Modic changes can be associated with lower back pain and disability. This review set out to explore why the literature to date has been conflicting. METHODS: A narrative, forensic, non-systematic literature review of selected articles to investigate why the published literature investigating the association between Modic imaging changes and chronic low back pain is inconsistent. RESULTS: This review found that previous systematic reviews and meta-analyses included both heterogeneous study designs and diverse patient syndromes resulting in an inconsistent association between Modic changes and nonspecific chronic lower back pain. Re-analysis of literature data focussing on more homogenous patient populations provides clearer evidence that Modic changes are associated with nonspecific chronic lower back pain and that type 1 Modic changes are more painful than type 2. CONCLUSIONS: Studies using tightly defined homogenous patient groups may provide the best test for association between MRI-findings and pain and disability. Clinical benefit of basivertebral nerve ablation observed in randomised controlled trials further supports the association between type 1 and type 2 Modic changes with pain and disability.
Asunto(s)
Dolor Crónico , Dolor de la Región Lumbar , Humanos , Dolor de la Región Lumbar/diagnóstico por imagen , Dolor de la Región Lumbar/terapia , Vértebras Lumbares , Imagen por Resonancia Magnética , Proyectos de Investigación , Dolor Crónico/diagnóstico por imagenRESUMEN
There is an urgent global need for new strategies and drugs to control and treat multidrug-resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes "traditional" and "nontraditional" antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 nontraditional), with 28 in phase 1, 32 in phase 2, 12 in phase 3, and 4 under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) were against mycobacteria, 15 (20%) were against C. difficile, and 4 (5%) were nontraditional agents with broad-spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores, and 4 of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens. We believe that future antibacterial research and development (R&D) should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.
Asunto(s)
Infecciones Bacterianas , Clostridioides difficile , Infecciones por Bacterias Gramnegativas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , HumanosRESUMEN
The contribution of bacterial infection to chronic low back pain and its treatment with antibiotics have generated considerable controversy in literature. If efficacious, antibiotics have the potential to transform the treatment of chronic low back pain in a significant subset of patients. Some microbiology studies of disc tissue from patients with CLBP have shown that bacteria are present, most likely due to infection, while others conclude they are absent or if found, it is due to surgical contamination. Clinical studies testing the efficacy of oral antibiotics to treat CLBP have either shown that the treatment is efficacious leading to significantly reduced pain and disability or that their effect is modest and not clinically significant. Critical review of the literature on CLBP, bacterial infection and treatment with antibiotics identified five well-designed and executed microbiology studies characterizing bacteria in disc samples that demonstrate that bacteria do infect herniated disc tissue, but that the bacterial burden is low and may be below the limits of detection in some studies. Two randomized, controlled clinical trials evaluating oral antibiotics in patients with CLBP indicate that for certain subsets of patients, the reduction in pain and disability achieved with antibiotic therapy may be significant. In patients for whom other therapies have failed, and who might otherwise progress to disc replacement or fusion surgery, antibiotic therapy may well be an attractive option to reduce the individual suffering associated with this debilitating condition. Additional clinical research is recommended to refine the selection of patients with CLBP caused or complicated by bacterial infection and most likely to respond to antibiotics, to optimize antibiotic therapy to maximize patient benefit, to minimize and manage side effects, and to address legitimate concerns about antibiotic stewardship.
Asunto(s)
Infecciones Bacterianas , Dolor Crónico , Desplazamiento del Disco Intervertebral , Dolor de la Región Lumbar , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Humanos , Desplazamiento del Disco Intervertebral/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Vértebras LumbaresRESUMEN
Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high-resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than 2 orders of magnitude compared to their human homologue, demonstrating a route to the selective chemical inhibition of these bacterial targets.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Sondas Moleculares/química , Serina-ARNt Ligasa/antagonistas & inhibidores , Staphylococcus aureus/enzimología , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Estructura Molecular , Serina-ARNt Ligasa/químicaRESUMEN
The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the screen identified very few ARB hits, which were strain/drug specific. These ARB hits included antimetabolites (zidovudine, floxuridine, didanosine, and gemcitabine), anthracyclines (daunorubicin, mitoxantrone, and epirubicin), and psychoactive drugs (gabapentin, fluspirilene, and oxethazaine). These findings suggest that there are few approved drugs that could be directly repositioned as adjunct antibacterials, and these will need robust testing to validate efficacy.
Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Didanosina/farmacología , Farmacorresistencia Bacteriana Múltiple , Etanolaminas/farmacología , Floxuridina/farmacología , Bacterias Gramnegativas/genética , Pruebas de Sensibilidad Microbiana , Mitoxantrona/farmacología , Zidovudina/farmacologíaRESUMEN
This analysis of the global clinical antibacterial pipeline was done in support of the Global Action Plan on Antimicrobial Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, target, mode of action). As of July 1, 2018, 30 new chemical entity (NCE) antibacterial drugs, ten biologics, ten NCEs against Mycobacterium tuberculosis, and four NCEs against C difficile were identified. Of the 30 NCEs, 11 are expected to have some activity against at least one critical priority pathogen expressing carbapenem resistance. The clinical pipeline is dominated by derivatives of established classes and most development candidates display limited innovation. New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and M tuberculosis.
Asunto(s)
Antituberculosos/uso terapéutico , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Carbapenémicos/efectos adversos , Carbapenémicos/uso terapéutico , Infecciones por Clostridium/microbiología , Farmacorresistencia Bacteriana/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Tuberculosis/microbiologíaRESUMEN
Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.
Asunto(s)
Antibacterianos/química , Descubrimiento de Drogas , Industria Farmacéutica/estadística & datos numéricos , Farmacorresistencia Microbiana , Antibacterianos/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Diseño de Fármacos , Industria Farmacéutica/economía , Industria Farmacéutica/legislación & jurisprudencia , Humanos , InvestigaciónRESUMEN
Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.
Asunto(s)
Antibacterianos/uso terapéutico , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/prevención & control , Farmacorresistencia Bacteriana/efectos de los fármacos , Drogas en Investigación/uso terapéutico , Vacunas/uso terapéutico , HumanosRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Girasa de ADN/metabolismo , Diseño de Fármacos , Inhibidores de Topoisomerasa II/farmacología , Urea/análogos & derivados , Urea/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Bacterias/enzimología , Bacterias/metabolismo , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química , Urea/síntesis química , Urea/químicaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Benzamidas/farmacología , Proteínas del Citoesqueleto/antagonistas & inhibidores , Diseño de Fármacos , Oxazoles/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Benzamidas/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazoles/química , Staphylococcus aureus/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , Diseño de Fármacos , Ácidos Isonipecóticos/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Benzotiazoles/síntesis química , Girasa de ADN/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/enzimología , Activación Enzimática/efectos de los fármacos , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/enzimología , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/enzimología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacocinéticaRESUMEN
The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 µg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 µg/ml for Streptococcus pneumoniae to 0.25 µg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10(-10) with compound A and <5.8 × 10(-11) with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Benzotiazoles/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , ADN-Topoisomerasas de Tipo II/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de Topoisomerasa/farmacología , Urea/análogos & derivados , Adenosina Trifosfatasas/antagonistas & inhibidores , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Benzotiazoles/química , Benzotiazoles/farmacocinética , Supervivencia Celular/efectos de los fármacos , Topoisomerasa de ADN IV/genética , Topoisomerasa de ADN IV/metabolismo , ADN-Topoisomerasas de Tipo II/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Bacterias Gramnegativas/enzimología , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/enzimología , Bacterias Grampositivas/crecimiento & desarrollo , Células Hep G2 , Humanos , Interleucina-33 , Interleucinas , Levofloxacino/farmacología , Masculino , Pruebas de Sensibilidad Microbiana , Novobiocina/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Inhibidores de Topoisomerasa/química , Inhibidores de Topoisomerasa/farmacocinética , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 µg/ml against all staphylococcal species, including methicillin- and multidrug-resistant Staphylococcus aureus and Staphylococcus epidermidis. Compound 1 inhibited an S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in a murine model of systemic S. aureus infection and caused a significant decrease in the bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was designated compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.
Asunto(s)
Antibacterianos/farmacocinética , Proteínas Bacterianas/antagonistas & inhibidores , Benzamidas/farmacocinética , Proteínas del Citoesqueleto/antagonistas & inhibidores , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Oxazoles/farmacocinética , Profármacos/farmacocinética , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus epidermidis/efectos de los fármacos , Succinatos/farmacocinética , Administración Oral , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Recuento de Colonia Microbiana , Citocinesis/efectos de los fármacos , Proteínas del Citoesqueleto/genética , Farmacorresistencia Bacteriana Múltiple , Femenino , Inyecciones Intravenosas , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Ratones , Pruebas de Sensibilidad Microbiana , Mutación , Oxazoles/síntesis química , Oxazoles/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis/crecimiento & desarrollo , Succinatos/síntesis química , Succinatos/farmacología , Ácido Succínico/química , Muslo/microbiología , Resultado del TratamientoRESUMEN
Cell division in almost all bacteria is orchestrated by the essential tubulin homologue FtsZ, which assembles into a ring-like structure and acts as a scaffold for the division machinery. Division was recently validated as an important target for antibiotics by the demonstration that low-molecular-weight inhibitors of FtsZ, called benzamides, can cure mice infected with Staphylococcus aureus. In treated cells of Bacillus subtilis we show that FtsZ assembles into foci throughout the cell, including abnormal locations at the cell poles and over the nucleoid. These foci are not inactive aggregates because they remain dynamic, turning over almost as rapidly as untreated polymers. Remarkably, although division is completely blocked, the foci efficiently recruit division proteins that normally co-assemble with FtsZ. However, they show no affinity for components of the Min or Nucleoid occlusion systems. In vitro, the benzamides strongly promote the polymerization of FtsZ, into hyperstable polymers, which are highly curved. Importantly, even at low concentrations, benzamides transform the structure of the Z ring, resulting in abnormal helical cell division events. We propose that benzamides act principally by promoting an FtsZ protomer conformation that is incompatible with a higher-order level of assembly needed to make a division ring.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Benzamidas/farmacología , Proteínas del Citoesqueleto/metabolismo , Bacillus subtilis/citología , Bacillus subtilis/efectos de los fármacos , Bacillus subtilis/metabolismo , Bacillus subtilis/ultraestructura , División Celular/efectos de los fármacos , División Celular/genética , Recuperación de Fluorescencia tras Fotoblanqueo , Microscopía Electrónica , Microscopía Fluorescente , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/metabolismoRESUMEN
3-Methoxybenzamide (1) is a weak inhibitor of the essential bacterial cell division protein FtsZ. Alkyl derivatives of 1 are potent antistaphylococcal compounds with suboptimal drug-like properties. Exploration of the structure-activity relationships of analogues of these inhibitors led to the identification of potent antistaphylococcal compounds with improved pharmaceutical properties.