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2.
ACS Infect Dis ; 7(4): 894-905, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33688718

RESUMEN

Novel polymyxin derivatives are often classified either as having direct activity against Gram-negative pathogens or as compounds inactive in their own right, which through permeabilization of the outer membrane act as potentiators of other antibiotics. Here, we report the systematic investigation of the influence of lipophilicity on microbiological activity (including against strains with reduced susceptibility to polymyxins), potentiation of rifampicin, and in vitro toxicity within a series of next-generation polymyxin nonapeptides. We demonstrate that the lipophilicity at the N-terminus and amino acids 6 and 7 in the cyclic peptide core is interchangeable and that the activity, ability to potentiate, and cytotoxicity all appear to be primarily driven by overall lipophilicity. Our work also suggests that the characterization of a polymyxin molecule as either a direct acting compound or a potentiator is more of a continuum that is strongly influenced by lipophilicity rather than as a result of fundamentally different modes-of-action.


Asunto(s)
Polimixinas , Rifampin , Antibacterianos/farmacología , Polimixinas/farmacología , Rifampin/farmacología
3.
Mar Drugs ; 19(2)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670308

RESUMEN

To tackle the growing problem of antibiotic resistance, it is essential to identify new bioactive compounds that are effective against resistant microbes and safe to use. Natural products and their derivatives are, and will continue to be, an important source of these molecules. Sea sponges harbour a diverse microbiome that co-exists with the sponge, and these bacterial communities produce a rich array of bioactive metabolites for protection and resource competition. For these reasons, the sponge microbiota constitutes a potential source of clinically relevant natural products. To date, efforts in bioprospecting for these compounds have focused predominantly on sponge specimens isolated from shallow water, with much still to be learned about samples from the deep sea. Here we report the isolation of a new Micromonospora strain, designated 28ISP2-46T, recovered from the microbiome of a mid-Atlantic deep-sea sponge. Whole-genome sequencing reveals the capacity of this bacterium to produce a diverse array of natural products, including kosinostatin and isoquinocycline B, which exhibit both antibiotic and antitumour properties. Both compounds were isolated from 28ISP2-46T fermentation broths and were found to be effective against a plethora of multidrug-resistant clinical isolates. This study suggests that the marine production of isoquinocyclines may be more widespread than previously supposed and demonstrates the value of targeting the deep-sea sponge microbiome as a source of novel microbial life with exploitable biosynthetic potential.


Asunto(s)
Antibacterianos/aislamiento & purificación , Microbiota , Micromonospora/aislamiento & purificación , Poríferos/microbiología , Animales , Antibacterianos/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Océano Atlántico , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Secuenciación Completa del Genoma
4.
FEMS Microbiol Lett ; 367(22)2020 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-33186989

RESUMEN

The use of bacterial transposon mutant libraries in phenotypic screens is a well-established technique for determining which genes are essential or advantageous for growth in conditions of interest. Standard, inactivating, transposon libraries cannot give direct information about genes whose over-expression gives a selective advantage. We report the development of a system wherein outward-oriented promoters are included in mini-transposons, generation of transposon mutant libraries in Escherichia coli and Pseudomonas aeruginosa and their use to probe genes important for growth under selection with the antimicrobial fosfomycin, and a recently-developed leucyl-tRNA synthase inhibitor. In addition to the identification of known mechanisms of action and resistance, we identify the carbon-phosphorous lyase complex as a potential resistance liability for fosfomycin in E. coli and P. aeruginosa. The use of this technology can facilitate the development of novel mechanism-of-action antimicrobials that are urgently required to combat the increasing threat worldwide from antimicrobial-resistant pathogenic bacteria.


Asunto(s)
Elementos Transponibles de ADN/genética , Farmacorresistencia Bacteriana/genética , Escherichia coli/genética , Regiones Promotoras Genéticas/genética , Pseudomonas aeruginosa/genética , Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Biblioteca de Genes , Pseudomonas aeruginosa/efectos de los fármacos
5.
Bioorg Med Chem Lett ; 30(11): 127163, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32273214

RESUMEN

Synthetic modifications have been made directly to the cyclic peptide core of polymyxin B, enabling the further understanding of structure activity relationships of this antimicrobial peptide. Such modified polymyxins are also substrates for enzymic hydrolysis, enabling the synthesis of a variety of semi-synthetic analogues, resulting in compounds with increased in vitro antibacterial activity.


Asunto(s)
Antibacterianos/química , Polimixina B/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Humanos , Hidrólisis , Pruebas de Sensibilidad Microbiana , Péptidos Cíclicos/química , Polimixina B/síntesis química , Polimixina B/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Relación Estructura-Actividad
6.
ACS Infect Dis ; 5(10): 1645-1656, 2019 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-31525992

RESUMEN

Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series of promising next generation polymyxin nonapeptides identified on the basis of our understanding of the relationship of structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that nonapeptides with an amine-containing N-terminal moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared to polymyxin B. We further demonstrate that compounds with a ß-branched aminobutyrate N-terminus with an aryl substituent offer a promising combination of low cytotoxicity and kidney exposure, leading to low toxicity in the mouse. From this series, SPR206 has been selected as a development candidate.


Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Polimixinas/síntesis química , Polimixinas/farmacología , Aminobutiratos , Animales , Línea Celular/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Polimixina B/farmacología
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