RESUMEN
Infections associated with antimicrobial resistance (AMR) are poised to become the leading cause of death in the next few decades, a scenario that can be ascribed to two phenomena: antibiotic over-prescription and a lack of antibiotic drug development. The crowd-sourced initiative Community for Open Antimicrobial Drug Discovery (CO-ADD) has been testing research compounds contributed by researchers around the world to find new antimicrobials to combat AMR, and during this campaign has found that metallodrugs might be a promising, yet untapped source. To this end, we submitted 18 PdII - and RuII -pyridyl-1,2,3-triazolyl complexes that were developed as catalysts to assess their antimicrobial properties. It was found that the Pd complexes, especially Pd1, possessed potent antifungal activity with MICs between 0.06 and 0.125â µg mL-1 against Candida glabrata. The in-vitro studies were extended to in-vivo studies in Galleria mellonella larvae, where it was established that the compounds were nontoxic. Here, we effectively demonstrate the potential of PdII -pyta complexes as antifungal agents.
Asunto(s)
Antiinfecciosos , Antiinfecciosos/farmacología , Antifúngicos/farmacología , Antibacterianos , Pruebas de Sensibilidad MicrobianaRESUMEN
Bacteria, similar to most organisms, have a love-hate relationship with metals: a specific metal may be essential for survival yet toxic in certain forms and concentrations. Metal ions have a long history of antimicrobial activity and have received increasing attention in recent years owing to the rise of antimicrobial resistance. The search for antibacterial agents now encompasses metal ions, nanoparticles and metal complexes with antimicrobial activity ('metalloantibiotics'). Although yet to be advanced to the clinic, metalloantibiotics are a vast and underexplored group of compounds that could lead to a much-needed new class of antibiotics. This Review summarizes recent developments in this growing field, focusing on advances in the development of metalloantibiotics, in particular, those for which the mechanism of action has been investigated. We also provide an overview of alternative uses of metal complexes to combat bacterial infections, including antimicrobial photodynamic therapy and radionuclide diagnosis of bacterial infections.
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Antiinfecciosos , Infecciones Bacterianas , Complejos de Coordinación , Humanos , Antibacterianos/farmacología , Complejos de Coordinación/farmacología , Farmacorresistencia Bacteriana , Antiinfecciosos/farmacología , Metales/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Iones/farmacologíaRESUMEN
On an annual basis the flagellate protozoan, Giardia duodenalis, is responsible for an estimated one billion human infections of which approximately two hundred million cause disease. However, the treatment of Giardia infections is reliant on a small group of chemotherapeutic classes that have a broad spectrum of antimicrobial activity and increasing treatment failure rates. To improve this situation, we need new drugs. In this study we screened the Compounds Australia Scaffolds Library for compounds with potent and selective activity against these parasites. Unlike previous drug discovery efforts that have focused on drug repurposing, this library is comprised of commercially available synthetic compounds arranged into lead-like scaffolds to facilitate structure activity relationship assessments and de novo drug discovery. A screen of 2451 compounds in this library identified 40 hits (>50% inhibitory activity at 10 µM, over 48 h). Secondary testing identified three compounds with IC50 values <1 µM and >50-fold selectivity for parasites over mammalian cells and a hit series, CL9406, comprising compounds with potent (lowest IC50 180 nM) and selective activity for Giardia parasites. The most promising compound in this series, SN00797640, displayed selective activity against assemblage A, B, and metronidazole resistant parasites which was parasiticidal (minimum lethal concentration 625 nM) and synergistic with albendazole. SN00797640 was well-tolerated when administered to mice at doses of 50 mg/kg daily for three days paving the way for pre-clinical in vivo activity assessment.
RESUMEN
There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 µM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.
RESUMEN
Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.
Asunto(s)
Antiinfecciosos , Infecciones por Bacterias Grampositivas , Staphylococcus aureus Resistente a Meticilina , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacología , Biopelículas , Glicopéptidos/farmacología , Glicopéptidos/uso terapéutico , Lipoglucopéptidos/uso terapéutico , Mamíferos , Ratones , Pruebas de Sensibilidad Microbiana , Streptococcus pneumoniae , Vancomicina/farmacología , Vancomicina/uso terapéuticoRESUMEN
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 µg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 µg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 µg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 µg/mL against Staphylococcus aureus.
Asunto(s)
Acrilonitrilo , Staphylococcus aureus Resistente a Meticilina , Acrilonitrilo/química , Amino Alcoholes , Antibacterianos/química , Antifúngicos/química , Escherichia coli , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Piperazina , Pseudomonas aeruginosa , Staphylococcus aureus , Relación Estructura-ActividadRESUMEN
Metallodrug discovery has evolved in recent years, yielding several compounds in the clinic for therapeutic and medical imaging diagnostic applications. As reviewed here, several research groups in well-established medicinal inorganic chemistry groups are consistently generating high-quality SAR data representing an ideal starting point in the use of computational methods to advance the development of new drugs. Although there are representative chemical structures of metallodrugs in public databases annotated with biological activity, there is currently no public compound database dedicated to metallodrugs. Here, we also discuss the significance, viability, applications and challenges of developing a public compound database of metallodrugs - with consistent representation of metallodrug structure being a crucial obstacle. A curated metallo-compound database would substantially benefit metallodrug discovery and development.
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Química Inorgánica , Química Farmacéutica , InformáticaRESUMEN
Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to ß-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections. IMPORTANCE Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort ß-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. During the on-going COVID-19 pandemic, secondary bacterial infection by A. baumannii has been associated with a 2-fold increase in COVID-19-related mortality. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation.
Asunto(s)
Infecciones por Acinetobacter , Acinetobacter baumannii , COVID-19 , Neumonía Asociada al Ventilador , Humanos , Animales , Ratones , Tigeciclina/farmacología , Neumonía Asociada al Ventilador/tratamiento farmacológico , Neumonía Asociada al Ventilador/microbiología , Tetraciclina/farmacología , Pandemias , Infecciones por Acinetobacter/microbiología , Farmacorresistencia Bacteriana Múltiple , Antibacterianos/farmacología , Carbapenémicos/farmacología , beta-Lactamas/farmacología , Pruebas de Sensibilidad Microbiana , Zinc/farmacologíaRESUMEN
Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome. To assess our design strategy, we tested all candidates for in vitro inhibitory activity and then evaluated them in vivo with several antibiotic-resistant strains to determine minimal inhibitory concentrations. The predicted best candidate is synthetically more accessible, exhibits higher solubility and binding affinity to the ribosome, and is up to 56 times more active against resistant pathogens than telithromycin. Notably, the best compounds designed by us show activity, especially when combined with the membrane-weakening drug colistin, against Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli, which are the three most critical targets from the priority list of pathogens of the World Health Organization.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Macrólidos/farmacología , Colistina/farmacología , Pruebas de Sensibilidad Microbiana/métodosRESUMEN
A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58-85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All compounds were characterized by 1H NMR, 13C NMR, and LC-MS. The conducted screening studies of the in vitro antimicrobial activity of the new quaternary salts derivatives established that 15 of the 18 newly synthesized compounds show antibacterial and antifungal activity. Synthesized 3-(3,4-dichlorohenyl)-1-[(4-phenoxyphenylcarbamoyl)-methyl]-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium chloride 6c possessed a broad activity spectrum towards Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Cryptococcus neoformans, with a high hemolytic activity against human red blood cells and cytotoxicity against HEK-293. However, compound 6c is characterized by a low in vivo toxicity in mice (LD50 > 2000 mg/kg).
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Antibacterianos/síntesis química , Antifúngicos/síntesis química , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Hongos/efectos de los fármacos , Células HEK293 , Humanos , Imidazoles/síntesis química , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Sales (Química)/síntesis química , Sales (Química)/química , Sales (Química)/farmacología , Relación Estructura-ActividadRESUMEN
Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of metal-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclooctadiene (COD) complexes. Amongst the 15 compounds studied, the simplest compounds Pt(COD)X2 (X=Cl, I, Pt1 and Pt2) showed excellent activity against a panel of Gram-positive bacteria including vancomycin and methicillin resistant Staphylococcus aureus. Additionally, the lead compounds show no toxicity against mammalian cells or haemolytic properties at the highest tested concentrations, indicating that the observed activity is specific against bacteria. Finally, these compounds showed no toxicity against Galleria mellonella at the highest measured concentrations. However, preliminary efficacy studies in the same animal model found no decrease in bacterial load upon treatment with Pt1 and Pt2. Serum exchange studies suggest that these compounds exhibit high serum binding which reduces their bioavailability inâ vivo, mandating alternative administration routes such as e. g. topical application.
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Alcadienos/farmacología , Complejos de Coordinación/farmacología , Bacterias Grampositivas/efectos de los fármacos , Platino (Metal)/farmacología , Alcadienos/química , Animales , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mariposas Nocturnas , Platino (Metal)/química , Relación Estructura-ActividadRESUMEN
Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol's primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the 'urgent threat' pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.
Asunto(s)
Antibacterianos/farmacología , Cannabidiol/análogos & derivados , Cannabidiol/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Animales , Antibacterianos/química , Cannabidiol/química , Cannabidiol/toxicidad , Clostridioides difficile/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Femenino , Células HEK293 , Hemólisis/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Neisseria gonorrhoeae/efectos de los fármacos , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Relación Estructura-ActividadRESUMEN
Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug-resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it is reasonable to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad-spectrum antifungal activity. Some of these complexes show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report the first inâ vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266â mg kg-1 are tolerated without adverse effects, paving the way for further inâ vivo studies of these complexes.
Asunto(s)
Antifúngicos/farmacología , Antibacterianos/farmacología , Candida , Cobalto , Complejos de Coordinación/toxicidad , Humanos , Pruebas de Sensibilidad Microbiana , Bases de SchiffRESUMEN
New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 µg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.
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Antiinfecciosos/farmacología , Educación/organización & administración , Relaciones Interinstitucionales , Afiliación Organizacional , Humanos , Pruebas de Sensibilidad Microbiana , Reproducibilidad de los ResultadosRESUMEN
Novel 1-aryl-3-biphenyl-4-yl-3-hydroxy-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-1-ium bromides and their 2,5-dehydrogenated analogues were designed and synthesized using a reaction of aryl-(4,5,6,7-tetrahydro-3H-azepin-2-yl)-amines with 1-biphenyl-4-yl-2-bromoethanone. Among the 16 novel compounds 5 derivatives displayed in vitro antimicrobial activity; while three of them showed promising activity against Staphylococcus aureus, Cryptococcus neoformans and Candida albicans.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Azepinas/farmacología , Imidazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Antifúngicos/síntesis química , Antifúngicos/toxicidad , Azepinas/síntesis química , Azepinas/toxicidad , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Células HEK293 , Hemólisis/efectos de los fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/toxicidad , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The discovery of novel antibiotics is essential to combat the rise of antimicrobial resistance. While a number of initiatives are focused on advancing promising leads into the clinic, there is a dearth of effort at stimulating the early stage discovery. We present one pathway that has successfully demonstrated an ability to revitalize fundamental research and reengage researchers.
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Antibacterianos , Antibacterianos/farmacología , Antibacterianos/uso terapéuticoRESUMEN
Peptide antibiotics are an abundant and synthetically tractable source of molecular diversity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their clinical development. Here we report structure-guided optimization of an amphipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina. The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC, a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3-4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the 'no observable adverse effect level' (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.
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Antibacterianos/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Animales , Carbapenémicos/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Colistina/farmacología , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Femenino , Proteínas del Helminto/química , Proteínas del Helminto/farmacología , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Peritonitis/tratamiento farmacológico , Peritonitis/microbiología , Neumonía/tratamiento farmacológico , Neumonía/microbiología , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiologíaRESUMEN
The formation of biofilms provides a formidable defense for many bacteria against antibiotics and host immune responses. As a consequence, biofilms are thought to be the root cause of most chronic infections, including those occurring on medical indwelling devices, endocarditis, urinary tract infections, diabetic and burn wounds, and bone and joint infections. In cystic fibrosis (CF), chronic Pseudomonas aeruginosa (P. aeruginosa) respiratory infections are the leading cause of morbidity and mortality in adults. Previous studies have shown that many bacteria can undergo a coordinated dispersal event in the presence of low concentrations of nitric oxide (NO), suggesting that NO could be used to initiate biofilm dispersal in chronic infections, enabling clearance of the more vulnerable planktonic cells. In this study, we describe efforts to create "all-in-one" cephalosporin-based NO donor prodrugs (cephalosporin-3'-diazeniumdiolates, C3Ds) that show both direct ß-lactam mediated antibacterial activity and antibiofilm effects. Twelve novel C3Ds were synthesized and screened against a panel of P. aeruginosa CF clinical isolates and other human pathogens. The most active compound, AMINOPIP2 ((Z)-1-(4-(2-aminoethyl)piperidin-1-yl)-2-(((6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methoxy)diazene 1-oxide)-ceftazidime 12, showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against ß-lactamases, activity against ceftazidime-resistant P. aeruginosa in vitro biofilms, and efficacy equivalent to ceftazidime in a murine P. aeruginosa respiratory infection model. The results support further evaluation of AMINOPIP2-ceftazidime 12 for P. aeruginosa lung infections in CF and a broader study of "all-in-one" C3Ds for other chronic infections.
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Fibrosis Quística , Infecciones del Sistema Respiratorio , Adulto , Animales , Antibacterianos/farmacología , Compuestos Azo , Biopelículas , Cefalosporinas/farmacología , Humanos , Ratones , Pseudomonas aeruginosaRESUMEN
There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.