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1.
Chemistry ; 26(13): 2852-2858, 2020 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-31788867

RESUMEN

New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal complexes offer access to alternative modes of action but have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug-resistant S. aureus and E. coli. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.


Asunto(s)
Antibacterianos/farmacología , Complejos de Coordinación/química , Escherichia coli/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Renio/química , Antibacterianos/química , Complejos de Coordinación/farmacología , Escherichia coli/química , Staphylococcus aureus Resistente a Meticilina/química , Staphylococcus aureus/efectos de los fármacos
2.
Biomacromolecules ; 19(12): 4629-4640, 2018 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-30359516

RESUMEN

There is growing interest in synthetic polymers which co-opt the structural features of naturally occurring antimicrobial peptides. However, our understanding of how macromolecular architecture affects antibacterial activity remains limited. To address this, we investigated whether varying architectures of a series of block and statistical co-oligomers influenced antibacterial and hemolytic activity. Cu(0)-mediated polymerization was used to synthesize oligomers constituting 2-(Boc-amino)ethyl acrylate units and either diethylene glycol ethyl ether acrylate (DEGEEA) or poly(ethylene glycol) methyl ether acrylate units with varying macromolecular architecture; subsequent deprotection produced primary amine functional oligomers. Further guanylation provided an additional series of antimicrobial candidates. Both chemical composition and macromolecular architecture were shown to affect antimicrobial activity. A broad spectrum antibacterial oligomer (containing guanidine moieties and DEGEEA units) was identified that possessed promising activity (MIC = 2 µg mL-1) toward both Gram-negative and Gram-positive bacteria. Bacterial membrane permeabilization was identified as an important contributor to the mechanism of action.


Asunto(s)
Alquilantes/química , Antibacterianos/química , Péptidos Catiónicos Antimicrobianos/química , Estructura Molecular , Acrilatos/química , Acrilatos/farmacología , Alquilantes/farmacología , Alquilación , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Cationes/química , Cationes/farmacología , Sustancias Macromoleculares/química , Sustancias Macromoleculares/farmacología , Pruebas de Sensibilidad Microbiana , Polimerizacion/efectos de los fármacos , Polímeros/química , Relación Estructura-Actividad
3.
Angew Chem Int Ed Engl ; 56(29): 8495-8499, 2017 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-28513074

RESUMEN

Δ-Myrtoxin-Mp1a (Mp1a), a 49-residue heterodimeric peptide from the venom of Myrmecia pilosula, comprises a 26-mer A chain and a 23-mer B chain connected by two disulfide bonds in an antiparallel arrangement. Combination of the individual synthetic chains through aerial oxidation remarkably resulted in the self-assembly of Mp1a as a homogenous product without the need for directed disulfide-bond formation. NMR analysis revealed a well-defined, unique structure containing an antiparallel α-helix pair. Dual polarization interferometry (DPI) analysis showed strong interaction with supported lipid bilayers and insertion within the bilayers. Mp1a caused non-specific Ca2+ influx in SH-SY5Y cells with a half maximal effective concentration (EC50 ) of 4.3 µm. Mp1a also displayed broad-spectrum antimicrobial activity, with the highest potency against Gram-negative Acinetobacter baumannii (MIC 25 nm). Intraplantar injection (10 µm) in mice elicited spontaneous pain and mechanical allodynia. Single- and two-chain mimetics of Mp1a revealed functional selectivity.


Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Péptidos/farmacología , Ponzoñas/química , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Hormigas , Calcio/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Péptidos/administración & dosificación , Péptidos/química
4.
Sci Transl Med ; 14(662): eabj2381, 2022 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-36103517

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 terapéutico
5.
Commun Biol ; 4(1): 7, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33469147

RESUMEN

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-Actividad
6.
J Mater Chem B ; 7(43): 6796-6809, 2019 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-31603181

RESUMEN

This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr2 and Me6TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-aminoethyl)-1,3-di-Boc-guanidine, 1-(3-aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 µg mL-1 (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C12 and 2C12 oligomers exhibiting greater lysis against the red blood cells (HC10 values between 7.1 and 43 µg mL-1) than their imidazole and tertiary amine counterparts (HC10 of >217 µg mL-1). Oligomers showed the greatest selectivity for C. neoformans, with the C12- and 2C12-tertiary amine and C12-imidazole oligomers possessing the greatest selectivity of >54-109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure-property relationships for antibacterial and antifungal materials.


Asunto(s)
Antibacterianos/uso terapéutico , Cloruro de Polivinilo/química , Antibacterianos/farmacología , Estructura Molecular , Relación Estructura-Actividad
7.
Nat Commun ; 9(1): 22, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29295973

RESUMEN

The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Daptomicina/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Vancomicina/farmacología , Animales , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Bacterias/clasificación , Supervivencia Celular/efectos de los fármacos , Glicopéptidos/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos
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