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Abstract(s)
Atualmente tem-se vindo a assistir a um uso inadequado dos antibióticos, resultando num aumento de resistências bacterianas, sendo Acinetobacter baumannii uma dessas bactéria. Esta bactéria é ubíqua e é isolada com frequência de equipamentos e superfícies hospitalares, onde é motivo de preocupação. A. baumannii está associada a infeções como pneumonias, septicémias, infeções urinárias e infeções nosocomiais essencialmente do foro respiratório com particular incidência em doentes que necessitam de ventilação artificial. A. baumannii possui diversos fatores de virulência e patogenicidade, capacidade de manter a sua viabilidade por longos períodos de tempo o que permite que se mantenha em ambientes hospitalares devido à sua capacidade de formar biofilmes e resistir à dessecação. Para além disso é uma bactéria que frequentemente apresenta múltiplas resistências a antibióticos, tendo sido isoladas estirpes com resistências a todos os antibióticos conhecidos. Estas características de A. baumannii fazem com que esta bactéria se torne um alvo preferencial para estudo e desenvolvimento de novas terapias alternativas devido à problemática das resistências à maioria dos antibióticos atualmente comercializados. O ácido barbitúrico é um composto orgânico baseado no esqueleto heterocíclico da pirimidina, sendo considerado farmacologicamente inativo, ao passo que os seus derivados têm demonstrado possuir várias atividades biológicas, incluindo propriedades antibacterianas em algumas bactérias gram positivas e negativas. Os compostos de síntese derivados do ácido barbitúrico, nomeadamente compostos como 5-hidraziniletilidenopirimidinas, podem ser assim uma alternativa promissora aos antibióticos convencionas. Assim, este trabalho teve como objetivos avaliar a potencial atividade antimicrobiana de seis compostos 5-hidraziniletilidenopirimidinas, derivados do ácido barbitúrico, sobre A. baumannii, quer em células planctónicas quer em biofilmes, assim como estudar o mecanismo de ação e potencial atividade hemolítica destes compostos neste microrganismo. Os resultados sugerem que as estirpes estudadas são suscetíveis aos compostos derivados do ácido barbitúrico com valores de concentração mínima inibitória entre 2 e > 32 µg/mL, sendo que estes têm um efeito bacteriostático em A. baumannii. Para além disso, a combinação dos compostos com os antibióticos tetraciclina, eritromicina, cloranfenicol, ciprofloxacina e gentamicina pode promover uma redução na concentração mínima inibitória dos antibióticos. Também foi evidenciado que os compostos não clivam ao ADN bacteriano, não inibem as bombas de efluxo e não inibem o processo de quorum-sensing, no entanto diminuem a motilidade bacteriana e inibem a formação de biofilmes. Estes compostos não apresentam capacidade hemolítica, indicando que não são citotóxicos para os eritrócitos humanos. Assim, os compostos de síntese derivados do ácido barbitúrico mostraram potencialidades in vitro promissoras para o controlo de infeções, redução da resistência aos antibióticos e inibição da formação de biofilmes bacterianos, podendo ter por isso potencial uso como agentes terapêuticos contra este microrganismo, com a particularidade de não apresentarem citotoxicidade em eritrócitos humanos.
Nowadays we have been assisting to an inadequate use of antibiotics, resulting in an increase of bacterial resistance, being Acinetobacter baumannii one of these cases. It is a ubiquitous bacterium, frequently isolated from equipment and surfaces from hospitals, where it has become subject of concern. A. baumannii is related with infections like pneumonias, septicaemias, urinary tract infections and nosocomial infections, especially respiratory stream infections in patients that need artificial ventilation. A. baumannii has several virulence and pathogenic factors, such as ability to maintain its viability for long periods of time that allow it to remain in hospital environment due to its capacity of biofilm formation and to resist dryness. This bacterium presents resistance to several antibiotics, and some of the isolated strains have been reported to be resistant to all known antibiotics. These A. baumannii’s characteristics makes this bacterium a target to the study and development of new alternative therapies due to the resistance to the majority of antibiotics being commercialized. Barbituric acid is an organic compound based on the pyrimidine heterocyclic skeleton, and it is pharmacological inactive, while its derivates have several biological activities. The synthetic compounds derivate from barbituric acid, like 5-hidrazinylethylidenpyrimidines, could be promising alternatives to conventional antibiotics. In this work, the potential antibacterial effect of six compounds 5-hidrazinylethylidenpyrimidines derivate from barbituric acid was evaluated against A. baumannii, either in planktonic cells or biofilm formation, quorum-sensing inhibition and bacterial motility. It was also studied the potential modulation of antibiotics’ resistance by the compounds in study, the potential efflux pump inhibition, DNA cleavage and hemolytic activity. Results suggest that the studied strains are susceptible to the synthetic compounds derivate from barbituric acid with minimum inhibitory concentration (MIC) ranging 2 to > 32 µg/mL. The studied compounds showed to have a bacteriostatic effect in A. baumannii. It was also possible to observe that the compounds do not cleave bacterial DNA, do not inhibit efflux pumps nor the quorum-sensing process. Also, the evaluated compounds have not shown hemolytic capacity, therefore they are not toxic to human erythrocytes. However, they reduce bacterial motility and inhibit biofilm formation. Besides this, the combination of the compounds with tetracycline, erythromycin, chloramphenicol, ciprofloxacin and gentamycin promote a reduction in the antibiotic MIC. With this, synthetic compounds derivate from barbituric acid studied here show promising in vitro applications in the control of infections, antibiotic resistance reduction and inhibition of bacterial biofilm formation. Thus, it could be possible to apply these compounds as antibacterial agents against this bacterium, with the advantage of lack of cytotoxicity against human erythrocytes.
Nowadays we have been assisting to an inadequate use of antibiotics, resulting in an increase of bacterial resistance, being Acinetobacter baumannii one of these cases. It is a ubiquitous bacterium, frequently isolated from equipment and surfaces from hospitals, where it has become subject of concern. A. baumannii is related with infections like pneumonias, septicaemias, urinary tract infections and nosocomial infections, especially respiratory stream infections in patients that need artificial ventilation. A. baumannii has several virulence and pathogenic factors, such as ability to maintain its viability for long periods of time that allow it to remain in hospital environment due to its capacity of biofilm formation and to resist dryness. This bacterium presents resistance to several antibiotics, and some of the isolated strains have been reported to be resistant to all known antibiotics. These A. baumannii’s characteristics makes this bacterium a target to the study and development of new alternative therapies due to the resistance to the majority of antibiotics being commercialized. Barbituric acid is an organic compound based on the pyrimidine heterocyclic skeleton, and it is pharmacological inactive, while its derivates have several biological activities. The synthetic compounds derivate from barbituric acid, like 5-hidrazinylethylidenpyrimidines, could be promising alternatives to conventional antibiotics. In this work, the potential antibacterial effect of six compounds 5-hidrazinylethylidenpyrimidines derivate from barbituric acid was evaluated against A. baumannii, either in planktonic cells or biofilm formation, quorum-sensing inhibition and bacterial motility. It was also studied the potential modulation of antibiotics’ resistance by the compounds in study, the potential efflux pump inhibition, DNA cleavage and hemolytic activity. Results suggest that the studied strains are susceptible to the synthetic compounds derivate from barbituric acid with minimum inhibitory concentration (MIC) ranging 2 to > 32 µg/mL. The studied compounds showed to have a bacteriostatic effect in A. baumannii. It was also possible to observe that the compounds do not cleave bacterial DNA, do not inhibit efflux pumps nor the quorum-sensing process. Also, the evaluated compounds have not shown hemolytic capacity, therefore they are not toxic to human erythrocytes. However, they reduce bacterial motility and inhibit biofilm formation. Besides this, the combination of the compounds with tetracycline, erythromycin, chloramphenicol, ciprofloxacin and gentamycin promote a reduction in the antibiotic MIC. With this, synthetic compounds derivate from barbituric acid studied here show promising in vitro applications in the control of infections, antibiotic resistance reduction and inhibition of bacterial biofilm formation. Thus, it could be possible to apply these compounds as antibacterial agents against this bacterium, with the advantage of lack of cytotoxicity against human erythrocytes.
Description
Keywords
Ácido Barbitúrico Acinetobacter Baumannii Atividade Antibacteriana. Compostos Sintéticos Resistências