A carregar...
Publicação
Efflux pumps in acinetobacter baumannii: study of new 1-(1-NaphtylMethyl)-Piperazine analogs as potential inhibitors
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 1.18 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
Nos últimos anos, a Humanidade tem combatido um problema cada vez mais emergente: infeções bacterianas resistentes. O que foi outrora a solução faz agora parte do problema: antibióticos. Muitas espécies bacterianas tornaram-se resistentes a um largo expectro de moléculas e um desses exemplos é o bacilo Gram-negativo Acinetobacter baummannii – um patogénio responsável por infeções respiratórias e da pele em ambiente hospitalar.
Os pacientes crónicos e/ou sujeitos a dispositvos médicos invasivos como catétes ou ventiladores e ainda aqueles cujos tratamentos incluem diálise ou terapêutica antimicrobana nos últimos 90 dias, são os que apresentam maior risco de infeção.
A. baumannii apresenta um mecanismo de resistência baseado na extrusão de moléculas de antibiótico através das bombas localizadas na sua membrana. Estas bombas são chamadas bombas de efluxo e a sua presença diminui a susceptilibilidade de A. baumannii a algumas fluoroquinolonas como a ciprofloxacina, uma fluoroquinolona de segunda geração com um largo espectro de actividade antimicrobiana.
Portugal foi um dos países com as maiores taxas (entre 25% e 50%) de isolados invasivos com resistência a fluoroquinolonas em 2018. O desenvolvimento de novas moléculas requer o uso de tempo e recursos, pelo que é mais vantajoso o desenvolvimento de moléculas que permitam restabelecer o poder antimicrobiano das moléculas já conhecidas e estudadas.
No caso das bombas de efluxo, uma das vias possíveis consiste na utilização de moléculas que são denominadas de EPIs – Inibidores das Bombas de Efluxo que aorsentam actividade sinergística com as moléculas de antibiótico através da inativação das bombas de efluxo.
As bombas da família resistência, nodulação e divisão celular são uma das famílias em que estão agrupadas os vários tipos de bombas de efluxo, tendo a 1-(1-naftilmetil)-piperazina (NMP) um efeito inibidor nas bombas desta família em A. baumannii. A principal bomba de efluxo nesta bactéria Gram-negativa é a AdeABC e os genes que codificam para esta estrutura tripartida são os genes adeA, adeB e adeC cuja expressão se encontra sob o controlo do sistema de regulação de dois componentes AdeRS.
Neste estudo, testámos uma série de análogos de NMP e a sua capacidade para restaurar a atividade da ciprofloxacina em diferentes isolados de A. Baumannii, tendo ainda sido avaliada a expressão dos genes que codificam para estas bombas bem como os respectivos genes reguladores. Demonstrou-se que os EPIs que podiam reconstituir a atividade da ciprofloxacina contra A. baumannii foram aqueles cuja estrutura apresentava a amina deprotegida: . EPIs 2, 6,7 e 8.
In the past few years, humanity has struggled with an emergent problem: multidrug bacterial infections. What was then the solution has now become part of the problem – antibiotics. Many bacterial species have become resistant to a wide range of molecules and such example is the Gram-negative bacillus Acinetobacter baumannii – a pathogen responsible for respiratory and skin infections in hospital environment. Patients who are chronically ill and those who have invasive medica devices such as catheters, sutures, ventilators and those treatments such as dialysis or antimicrobial therapy in the past 90 days are at the highest risk of infection. A. baumannii has a mechanism of resistance based in the extrusion of antibiotic molecules throughout pumps located in its membrane. These pumps are called efflux pumps and they decrease the susceptibility of A. baumannii to some fluoroquinolones such as ciprofloxacin, a second-generation fluoroquinolone with a wide range of action. Portugal was one of the countries with the higher (25% to 50%) percentages of invasive isolates with resistance to fluroquinolones in 2018. The development of new drugs is time and resource consuming and so it is more profitable to develop new molecules that will restore efficacy to old already studied and safety to use antibiotics. These new molecules are called EPIs - Efflux Pump Inhibitors and they synergize with the antibiotic molecules by inactivating the efflux pumps in A. baumannii. Resistance-Nodulation-Division (RND) is one of the families of pumps in which the efflux pumps are grouped and 1-(1-naphthylmethyl)-piperazine (NMP) is one of the EPIs that have effect in inhibiting this pump in A. baumannii. The major efflux pump in these Gram negative species is the AdeABC and the encoding genes of these tripartite structures are adeA, adeB and adeC and whose expression is regulated by a two-component regulation system: AdeRS. In this study we tested a series of analogs of NMP and their ability to restore the antibiotic efficacy of ciprofloxacin in several isolates of A. baumannii and the genes that regulate these pumps. It was shown that the EPIs that could restore the activity of the ciprofloxacin against A. baumannii were the ones in which the amine was unprotected – the EPIs 2,6,7 and 8.
In the past few years, humanity has struggled with an emergent problem: multidrug bacterial infections. What was then the solution has now become part of the problem – antibiotics. Many bacterial species have become resistant to a wide range of molecules and such example is the Gram-negative bacillus Acinetobacter baumannii – a pathogen responsible for respiratory and skin infections in hospital environment. Patients who are chronically ill and those who have invasive medica devices such as catheters, sutures, ventilators and those treatments such as dialysis or antimicrobial therapy in the past 90 days are at the highest risk of infection. A. baumannii has a mechanism of resistance based in the extrusion of antibiotic molecules throughout pumps located in its membrane. These pumps are called efflux pumps and they decrease the susceptibility of A. baumannii to some fluoroquinolones such as ciprofloxacin, a second-generation fluoroquinolone with a wide range of action. Portugal was one of the countries with the higher (25% to 50%) percentages of invasive isolates with resistance to fluroquinolones in 2018. The development of new drugs is time and resource consuming and so it is more profitable to develop new molecules that will restore efficacy to old already studied and safety to use antibiotics. These new molecules are called EPIs - Efflux Pump Inhibitors and they synergize with the antibiotic molecules by inactivating the efflux pumps in A. baumannii. Resistance-Nodulation-Division (RND) is one of the families of pumps in which the efflux pumps are grouped and 1-(1-naphthylmethyl)-piperazine (NMP) is one of the EPIs that have effect in inhibiting this pump in A. baumannii. The major efflux pump in these Gram negative species is the AdeABC and the encoding genes of these tripartite structures are adeA, adeB and adeC and whose expression is regulated by a two-component regulation system: AdeRS. In this study we tested a series of analogs of NMP and their ability to restore the antibiotic efficacy of ciprofloxacin in several isolates of A. baumannii and the genes that regulate these pumps. It was shown that the EPIs that could restore the activity of the ciprofloxacin against A. baumannii were the ones in which the amine was unprotected – the EPIs 2,6,7 and 8.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
A. baumannii Efflux pump inhibitors NMP Antimicrobial resistance RND family AdeABC AdeRS Mestrado integrado -2020