Antibacterial Activity of a Cationic Antimicrobial Peptide against Multidrug-Resistant Gram-Negative Clinical Isolates and Their Potential Molecular Targets.

Antimicrobial resistance reduces the efficacy of antibiotics. Infections caused by multidrug-resistant (MDR), Gram-negative bacterial strains, such as Klebsiella pneumoniae (MDRKp) and Pseudomonas aeruginosa (MDRPa), are a serious threat to global health. However, cationic antimicrobial peptides (CAMPs) are promising as an alternative therapeutic strategy against MDR strains. In this study, the inhibitory activity of a cationic peptide, derived from cecropin D-like (ΔM2), against MDRKp and MDRPa clinical isolates, and its interaction with membrane models and bacterial genomic DNA were evaluated. In vitro antibacterial activity was determined using the broth microdilution test, whereas interactions with lipids and DNA were studied by differential scanning calorimetry and electronic absorption, respectively. A strong bactericidal effect of ΔM2 against MDR strains, with minimal inhibitory concentration (MIC) and minimal bactericidal concentrations (MBC) between 4 and 16 µg/mL, was observed. The peptide had a pronounced effect on the thermotropic behavior of the 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG) membrane models that mimic bacterial membranes. Finally, the interaction between the peptide and genomic DNA (gDNA) showed a hyperchromic effect, which indicates that ΔM2 can denature bacterial DNA strands via the grooves.

Synthesis, antibacterial activity and DNA interactions of lanthanide(IU) complexes of N(4)-substituted thiosemicarbazones / Síntesis, actividad antibacterial e interacciones con DNA de complejos lantánidos (III) de Tiosemicarbazonas N(4)-sustituídas / Síntese, atividade antibacteriana e interações com DNA de complexos lantanídeos (III) de tiosemicarbazonas N(4)-substituídas

Abstract This paper reports the synthesis and detailed characterization of six novel lanthanide complexes of La(III), Eu(III) and Nd(III) with N(4)-substituted thiosemicarbazones derived from the 2-carboxybenzaldehyde. The IR, 1H-NMR and 13C-NMR spectroscopic studies confirmed the coordination of the thiocarbonyl (C=S), azomethine (C=N) and carboxylate (COO-) groups to the metal centers, and the carboxylate was coordinated in a bidentate manner. The elemental and thermal analyses suggest that lanthanide complexes were formed in 1:2 molar ratios (metal:ligand). The molar conductivity values confirmed the non-electrolytic nature of the complexes. The interaction of these complexes with calf thymus DNA (CT-DNA) was investigated by UV absorption and viscosity measurements. It was found that the Eu(HI) and Nd(nI) complexes could roll along the DNA strands through groove interactions. Furthermore, lanthanide complexes could promote the oxidative cleavage of plasmid pBR322 in a high-oxidative stress environment. Finally, the Schiff base ligands (L) and their complexes were evaluated for their antibacterial activities against gram-positive and gram-negative bacteria using a microdilution procedure. The results indicate that the lanthanide complexes exhibit more potent antibacterial activity than the free ligands.

Resumen Este articulo reporta la síntesis y caracterización detallada de seis nuevos complejos lantánidos de La(III), Eu(III) y Nd(III) con tiosemicarbazonas N(4)-sustituidas derivadas del 2-carboxibenzaldehído. Los estudios espectroscópicos de IR, 1H-NMR y 13C-NMR confirmaron la coordinación de los grupos tiocarbonilo (C=S), azometina (C=N) y carboxilato (COO-) a los centros metálicos, y el carboxilato se coordinó de forma bidentada. Los análisis elemental y térmico sugieren que los complejos lantánidos se formaron en proporciones molares 1:2 (metal:ligando). Los valores de conductividad molar confirmaron la naturaleza no eléctrica de los complejos. Por medio de medidas de absorción UV y de viscosidad se investigó la interacción entre estos complejos con DNA de timo de ternera (CT-DNA). Se encontró que los complejos Eu(III) y Nd(III) podrían correr a lo largo de cadenas de DNA a través de interacciones en el surco. Además, los complejos lantánidos podrían promover el clivaje oxidativo del plásmido pBR322 en un ambiente de alto estrés oxidativo. Finalmente, se evaluaron las actividades antibacteriales de las bases de Schiff como ligandos (L) y sus complejos contra bacterias gram-positivas y gram-negativas usando un procedimiento de microdilución. Los resultados indican que los complejos lantánidos exhiben una actividad antibacterial más potente que los ligandos libres.

Resumo Este artigo reporta a síntese e caracterização detalhada de seis novos complexos lantanídeos de La(III), Eu(III) e Nd(III) com tiosemicarbazonas N(4)-substituídas derivadas do 2-carboxibenzaldeído. Os estudos espectroscópicos de IR, 1H-RMN e 13C-RMN confirmaram a coordenação dos grupos tiocarbonilos (C = S), azometina (C=N) e carboxilato (COO-) com os centros metálicos, e o carboxilato se coordenou de forma bidentada. As análises elementares e térmicas sugerem que os complexos lantanídeos se formaram em proporções molares 1:2 (metal:ligante). Os valores de condutividades molar confirmaram a natureza não-elétrica dos complexos. Se avaliou a interação entre estes complexos com DNA de vitela (CT-DNA) por meio de medidas de absorção UV e de viscosidade. Se observou que os complexos Eu(III) e Nd(III) poderiam deslocar-se ao longo da cadeia de DNA através de interações no sulco. Adicionalmente, os complexos lantanídeos poderiam promover a clivagem oxidativa do plasmídeo pBR322 em um ambiente de alto estresse oxidativo. Finalmente, se avaliaram as atividades antibacterianas das bases de Schiff como ligantes (L) e seus complexos contra bactérias gram-positivas e gram- negativas, usando o método de microdiluição. Os resultados indicam que os complexos lantanídeos exibem uma atividade antibacteriana mais potente que os ligantes livres.