A carregar...
Publicação
Insights on the mechanisms underlying the development of heteroresistance to colistin in Acinetobacter baumannii
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 1.62 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
A versatilidade de mecanismos de resistência, intrínsecos ou adquiridos, encontrados em
Acinetobacter baumannii são um constante desafio no que diz respeito ao combate às
infecções provocadas por estas bactérias. Para o tratamento de infecções provocadas por
estirpes de A. baumannii multirresistente (MDR), a colistina é geralmente a última opção
terapêutica. No entanto, isolados clínicos resistentes a quase todos os antibióticos
disponíveis, incluindo à colistina, têm vindo a ser reportados por todo o mundo. Alguns
destes isolados apresentam ainda heterorresistência à colistina, um fenómeno que consiste
na existência de uma população heterogénea com uma, ou várias subpopulações, com
diferentes níveis de resistência ao antibiótico, em comparação com a população
predominante da mesma estirpe. Os mecanismos subjacentes à heterorresistência à
colistina são complexos e diversificados entre diferentes espécies bacterianas, e pouco
compreendidos em A. baumannii. Neste estudo, três variantes isogénicas de uma estirpe
de A. baumannii MDR, produtora de carbapenemases, com heterorresistência à colistina,
variante L, variante S e variante XS, foram caracterizadas morfológica, fenotípica e
genotipicamente. O crescimento em meio Levine-agar suplementado com colistina
revelou diferentes morfologias de colónias entre as variantes, que por sua vez apresentam
diferentes perfis de resistência à colistina, diferentes taxas de crescimento, e um fenótipo
de heterorresistência estável. Estes resultados indicam que subpopulações
heterorresistentes à colistina poderão ser selecionadas mediante exposição ao antibiótico.
Todas as variantes apresentam um aumento da actividade de efluxo com respostas
diferentes perante o inibidor de efluxo tioridazina, colistina e brometo de etídio.
Nomeadamente, a variante L e a variante S demonstram sobreexpressão dos genes adeG,
craA, abeM e também para o gene abeS na variante S. Mutações no gene pmrB, que
codifica o regulador de dois componentes PmrAB envolvido na modificação de
lipopolissacáridos, e nos genes lpxC e lpxD responsáveis pela biossíntese do lípido A
foram observadas em todas as variantes. Este estudo evidência a presença de mais do que
um mecanismo envolvido no desenvolvimento da heterorresistência à colistina em A.
baumannii.
The versatility of intrinsic or acquired resistance mechanisms found in Acinetobacter baumannii is a constant challenge in combating infections caused by these bacteria. For the treatment of infections caused by multidrug-resistant (MDR) A. baumannii, colistin is usually the last therapeutic option. However, clinical isolates resistant to almost all available antibiotics, including colistin, have been reported worldwide. Some of these isolates also demonstrate the presence of heteroresistance to colistin, a phenomenon where there is a heterogeneous population with one or several sub-populations with different levels of antibiotic resistance compared to the main population in the same strain. The mechanisms underlying colistin heteroresistance are complex and diverse among different bacterial species, and poorly understood for A. baumannii. In this study, three isogenic strain-variants from a MDR A. baumannii carbapenemase-producing clinical isolate with simultaneous heteroresistance to colistin, strain-variant L, strain variant S, and strain-variant XS, were characterized morphologically, phenotypic, and genotypically. Growth on colistin-supplemented Levine-agar revealed strain-variants exhibiting different colony morphologies that showed different colistin resistance profiles, different growth rates and stable heteroresistance phenotype. This data indicates that subpopulations heteroresistant to colistin could be selected upon antibiotic exposure. All variants showed increased efflux activity with different responses to the interactions between the efflux inhibitor thioridazine, colistin and ethidium bromide. The L variant and the S variant exhibited overexpression of the adeG, craA, abeM genes and the abeS gene in the S variant. Mutations in the pmrB gene, which encodes for the two-component PmrAB regulator involved in the lipopolysaccharide modification, and in the lpxC and lpxD genes responsible for lipid A biosynthesis were observed in all variants. This study evidenced the existence of more than one mechanism engaged in colistin heteroresistance in A. baumannii.
The versatility of intrinsic or acquired resistance mechanisms found in Acinetobacter baumannii is a constant challenge in combating infections caused by these bacteria. For the treatment of infections caused by multidrug-resistant (MDR) A. baumannii, colistin is usually the last therapeutic option. However, clinical isolates resistant to almost all available antibiotics, including colistin, have been reported worldwide. Some of these isolates also demonstrate the presence of heteroresistance to colistin, a phenomenon where there is a heterogeneous population with one or several sub-populations with different levels of antibiotic resistance compared to the main population in the same strain. The mechanisms underlying colistin heteroresistance are complex and diverse among different bacterial species, and poorly understood for A. baumannii. In this study, three isogenic strain-variants from a MDR A. baumannii carbapenemase-producing clinical isolate with simultaneous heteroresistance to colistin, strain-variant L, strain variant S, and strain-variant XS, were characterized morphologically, phenotypic, and genotypically. Growth on colistin-supplemented Levine-agar revealed strain-variants exhibiting different colony morphologies that showed different colistin resistance profiles, different growth rates and stable heteroresistance phenotype. This data indicates that subpopulations heteroresistant to colistin could be selected upon antibiotic exposure. All variants showed increased efflux activity with different responses to the interactions between the efflux inhibitor thioridazine, colistin and ethidium bromide. The L variant and the S variant exhibited overexpression of the adeG, craA, abeM genes and the abeS gene in the S variant. Mutations in the pmrB gene, which encodes for the two-component PmrAB regulator involved in the lipopolysaccharide modification, and in the lpxC and lpxD genes responsible for lipid A biosynthesis were observed in all variants. This study evidenced the existence of more than one mechanism engaged in colistin heteroresistance in A. baumannii.
Descrição
Palavras-chave
Microbiologia médica Acinetobacter baumannii Colistina Efluxo Bombas de efluxo Heterorresistência