RESUMO
Antimicrobial resistance (AMR) poses a significant threat to global public health. Notably, resistance to carbapenem and extended-spectrum ß-lactam antibiotics in Gram-negative bacteria is a major impediment to treating infections. Genes responsible for antibiotic resistance are frequently carried on plasmids, which can transfer between bacteria. Therefore, exploring strategies to prevent this transfer and the prevalence of AMR plasmids is timely and pertinent. Here, we show that certain natural product extracts and associated pure compounds can reduce the conjugation of AMR plasmids into new bacterial hosts. Using our established high-throughput fluorescence-based flow cytometry assay, we found that the natural products were more active in reducing transmission of the IncK extended-spectrum ß-lactamase-encoding plasmid pCT in Escherichia coli EC958c, compared to Klebsiella pneumoniae Ecl8 carrying the IncFII carbapenemase-encoding plasmid pKpQIL. The exception was the natural product rottlerin, also active in K. pneumoniae. In classical conjugation assays, rottlerin also reduced the conjugation frequency of the IncFII bla NDM-1 carrying plasmid pCPE16_3 from a clinical K. pneumoniae isolate. Our data indicate that the natural products tested here, in their current molecular structure, reduced conjugation by a small amount, which is unlikely to achieve a large-scale reduction in AMR in bacterial populations. However, certain natural products like rottlerin could provide a foundation for further research into compounds with effective anti-plasmid activity.
Assuntos
Antibacterianos , Produtos Biológicos , Escherichia coli , Klebsiella pneumoniae , Plasmídeos , beta-Lactamases , Plasmídeos/genética , Antibacterianos/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , beta-Lactamases/genética , beta-Lactamases/metabolismo , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana/genética , Conjugação Genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Testes de Sensibilidade Microbiana , Microbiologia de Alimentos , Transferência Genética HorizontalRESUMO
Antimicrobial resistance (AMR) is a global threat, with evolution and spread of resistance to frontline antibiotics outpacing the development of novel treatments. The spread of AMR is perpetuated by transfer of antimicrobial resistance genes (ARGs) between bacteria, notably those encoded by conjugative plasmids. The human gut microbiome is a known 'melting pot' for plasmid conjugation, with ARG transfer in this environment widely documented. There is a need to better understand the factors affecting the incidence of these transfer events, and to investigate methods of potentially counteracting the spread of ARGs. This review describes the use and potential of three approaches to studying conjugation in the human gut: observation of in situ events in hospitalized patients, modelling of the microbiome in vivo predominantly in rodent models, and the use of in vitro models of various complexities. Each has brought unique insights to our understanding of conjugation in the gut. The use and development of these systems, and combinations thereof, will be pivotal in better understanding the significance, prevalence, and manipulability of horizontal gene transfer in the gut microbiome.