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Avaliação da atividade antibacteriana de novos derivados da ciprofloxacina e da sulfonamida
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Abstract(s)
A introdução de antibióticos na prática clínica revolucionou a medicina no século XX,
contribuindo significativamente para o aumento da longevidade e da qualidade de vida.
Contudo, o uso inadequado e indiscriminado destes fármacos tem contribuído para o
agravamento da resistência antimicrobiana (RAM), atualmente reconhecida como uma das
principais ameaças à saúde pública mundial. A RAM compromete a eficácia do tratamento de
infeções bacterianas e origina custos significativos para os sistemas de saúde, sendo
responsável por mais de 35000 mortes anuais na União Europeia. Apesar de poucas ou
nenhumas novas classes de antibióticos terem sido introduzidas no mercado nas últimas
décadas, têm sido propostas e desenvolvidas novas estratégias e abordagens inovadoras, que
representam um sinal de esperança no combate à RAM.
As bactérias, como qualquer outro organismo, necessitam de ferro como cofator enzimático
para catalisar reações biológicas vitais. A absorção de ferro por estes organismos unicelulares é
alcançada através de vários mecanismos, nomeadamente a produção de pequenas moléculas
orgânicas quelantes de ferro denominadas sideróforos. Estes metabolitos são libertados pelas
bactérias de forma a sequestrar o ferro circundante e, através de recetores específicos,
incorporá-lo no seu citoplasma.
Uma das estratégias emergentes para a descoberta de novos antibióticos, designada de “Cavalo
de Tróia”, envolve a conjugação de antibióticos com sideróforos ou seus miméticos. Este
complexo é reconhecido pelos sistemas de captação de ferro da bactéria e, deste modo, o
antibiótico é transportado para dentro da célula bacteriana, contornando os mecanismos de
resistência antibiótica microbiana.
Neste contexto, a presente dissertação teve como objetivo avaliar a atividade antibacteriana de
novos antimicrobianos derivados da ciprofloxacina, uma fluoroquinolona, e da sulfonamida,
sintetizados, tendo por base a estratégia “Cavalo de Tróia”. Para tal, determinou-se a
concentração mínima inibitória (MIC) dos compostos em bactérias clinicamente relevantes,
nomeadamente: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli e Pseudomonas
aeruginosa. Neste trabalho também foi explorada a relação estrutura-atividade (SAR) dos novos
antibacterianos, visando correlacionar as modificações introduzidas nas estruturas das
moléculas da ciprofloxacina e sulfonamida com a eficácia antimicrobiana observada. No caso dos derivados da ciprofloxacina, o composto CIPSID9 revelou o perfil antimicrobiano
mais promissor, especialmente contra bactérias Gram-negativo, com MICs de 0,25 mg/L (E. coli),
4 mg/L (P. aeruginosa e S. aureus) e 8 mg/L (E. faecalis). Relativamente aos derivados da
sulfonamida, embora todos tenham exibido MICs iguais ou superiores a 64 mg/L, o composto
SULFA2DP destacou-se com o valor de MIC mais baixo contra a E. coli (MIC = 64 mg/L). Os
derivados CIPSID9, SULFA2DP e SULFA4 revelaram-se candidatos promissores para futuras
otimizações estruturais, destacando-se ainda pela potencial atividade quelante, associada à
presença de grupos com reconhecida capacidade quelante de ferro na sua estrutura, como os
grupos hidroxilo e catecol. Por fim, ensaios complementares confirmaram que concentrações
até 1% de DMSO podem ser utilizadas com segurança na solubilização dos compostos, uma vez
que não apresentaram um impacto significativo no crescimento bacteriano.
The introduction of antibiotics in clinical practice revolutionized medicine in the 20th century, significantly contributing to the increase in longevity and quality of life. However, the inappropriate and indiscriminate use of these drugs has contributed to the worsening of antimicrobial resistance (AMR), currently recognized as one of the main threats to global public health. AMR compromises the effectiveness of bacterial infections treatment and incurs significant costs for healthcare systems, being responsible for more than 35000 annual deaths in the European Union. Despite few or no new classes of antibiotics being introduced to the market in recent decades, new strategies and innovative approaches have been proposed and developed, representing a sign of hope in the fight against AMR. Bacteria, like any other organisms, need iron as an enzymatic cofactor to catalyze vital biological reactions. The absorption of iron by these unicellular organisms is achieved through various mechanisms, namely the production of small organic iron-chelating molecules called siderophores. These metabolites are released by bacteria in order to sequester the surrounding iron and, through specific receptors, incorporate it into their cytoplasm. One of the emerging strategies for the discovery of new antibiotics, designated as "Trojan Horse", involves the conjugation of antibiotics with siderophores or their mimetics. This complex is recognized by the bacterial iron uptake systems and, thus, the antibiotic is transported into the bacterial cell, circumventing the mechanisms of microbial antibiotic resistance. In this context, the present dissertation aimed to evaluate the antibacterial activity of new antimicrobials derived from ciprofloxacin, a fluoroquinolone, and sulfonamide, synthesized based on the “Trojan Horse” strategy. To this end, the minimum inhibitory concentration (MIC) of the compounds was determined in clinically relevant bacteria, namely: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. This work also explored the structure-activity relationship (SAR) of the new antibacterials, aiming to correlate the structural modifications introduced in the structures of the ciprofloxacin and sulfonamide molecules with the observed antimicrobial efficacy. In the case of ciprofloxacin derivatives, the compound CIPSID9 revealed the most promising antimicrobial profile, especially against Gram-negative bacteria, with MICs of 0.25 mg/L (E. coli), 4 mg/L (P. aeruginosa and S. aureus) and 8 mg/L (E. faecalis). Regarding the sulfonamide derivatives, although all exhibited MICs equal to or greater than 64 mg/L, the compound SULFA2DP stood out with the lowest MIC value against E. coli (MIC = 64 mg/L). The derivatives CIPSID9, SULFA2DP and SULFA4 proved to be promising candidates for future structural optimizations, also standing out for their potential chelating activity, associated with the presence of groups with recognized iron chelating capacity in their structure, such as hydroxyl and catechol groups. Finally, complementary tests confirmed that concentrations of up to 1% DMSO can be safely used to solubilize the compounds, since they didn’t present a significant impact on bacterial growth.
The introduction of antibiotics in clinical practice revolutionized medicine in the 20th century, significantly contributing to the increase in longevity and quality of life. However, the inappropriate and indiscriminate use of these drugs has contributed to the worsening of antimicrobial resistance (AMR), currently recognized as one of the main threats to global public health. AMR compromises the effectiveness of bacterial infections treatment and incurs significant costs for healthcare systems, being responsible for more than 35000 annual deaths in the European Union. Despite few or no new classes of antibiotics being introduced to the market in recent decades, new strategies and innovative approaches have been proposed and developed, representing a sign of hope in the fight against AMR. Bacteria, like any other organisms, need iron as an enzymatic cofactor to catalyze vital biological reactions. The absorption of iron by these unicellular organisms is achieved through various mechanisms, namely the production of small organic iron-chelating molecules called siderophores. These metabolites are released by bacteria in order to sequester the surrounding iron and, through specific receptors, incorporate it into their cytoplasm. One of the emerging strategies for the discovery of new antibiotics, designated as "Trojan Horse", involves the conjugation of antibiotics with siderophores or their mimetics. This complex is recognized by the bacterial iron uptake systems and, thus, the antibiotic is transported into the bacterial cell, circumventing the mechanisms of microbial antibiotic resistance. In this context, the present dissertation aimed to evaluate the antibacterial activity of new antimicrobials derived from ciprofloxacin, a fluoroquinolone, and sulfonamide, synthesized based on the “Trojan Horse” strategy. To this end, the minimum inhibitory concentration (MIC) of the compounds was determined in clinically relevant bacteria, namely: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. This work also explored the structure-activity relationship (SAR) of the new antibacterials, aiming to correlate the structural modifications introduced in the structures of the ciprofloxacin and sulfonamide molecules with the observed antimicrobial efficacy. In the case of ciprofloxacin derivatives, the compound CIPSID9 revealed the most promising antimicrobial profile, especially against Gram-negative bacteria, with MICs of 0.25 mg/L (E. coli), 4 mg/L (P. aeruginosa and S. aureus) and 8 mg/L (E. faecalis). Regarding the sulfonamide derivatives, although all exhibited MICs equal to or greater than 64 mg/L, the compound SULFA2DP stood out with the lowest MIC value against E. coli (MIC = 64 mg/L). The derivatives CIPSID9, SULFA2DP and SULFA4 proved to be promising candidates for future structural optimizations, also standing out for their potential chelating activity, associated with the presence of groups with recognized iron chelating capacity in their structure, such as hydroxyl and catechol groups. Finally, complementary tests confirmed that concentrations of up to 1% DMSO can be safely used to solubilize the compounds, since they didn’t present a significant impact on bacterial growth.
Description
Keywords
Antibiotics Antimicrobial resistance Ciprofloxacin Sulfonamide Minimum inhibitory concentration Structure-activity relationship Antibióticos Resistência antimicrobiana Ciprofloxacina Sulfonamida Concentração mínima inibitória Relação estrutura-atividade