Nimbolide from Azadirachta indica and its derivatives plus first-generation cephalosporin antibiotics: a novel drug combination for wound-infecting pathogens

Abstract

The shortage of effective drugs against wound infecting pathogens poses a serious public health threat. Combination treatment may represent a good choice for treating infections caused by these pathogens. The aim of the present study was to evaluate the in vitro efficacy of nimbolide, desacetylnimbin isolated from Azadirachta indica and the amide derivatives of nimbolide in combination with first generation cephalosporin antibiotics against major wound associated bacterial pathogens. The antibacterial activity of the compounds and antibiotics were studied by calculating minimum inhibitory concentration and minimum bactericidal concentration. The checkerboard and time-kill assay were used to evaluate the interactions between the compounds and antibiotics. Nimbolide recorded highest antimicrobial activity against all tested strains followed by desacetylnimbin but the amide derivatives of nimbolide were found to be less active. The MICs of test compounds ranged from 64 to 2000 µg/mL. In the checkerboard test, nimbolide and its derivatives markedly reduced the MIC values of the antibiotics. Significant synergistic effect was recorded by nimbolide as well as desacetylnimbin in combination with antibiotics and this combination recorded significant reduction of the colony forming units (CFUs) in time kill assay and the maximum reduction was recorded between 4 to 12 h. The above combination was also found to be effective against methicillin-resistant Staphylococcus aureus (MRSA), an important drug resistant bacterium. The cytotoxicity of the compounds was tested against H9c2 and recorded no toxicity up to 200 µM. In summary, the combination of nimbolide/desacetylnimbin and antibiotics demonstrated synergistic activity against the major wound associated bacteria tested in this study. Furthermore, these compounds may potentially widen the therapeutic window of antibiotics, suggesting that these combinations could be used clinically to control infections caused by wound pathogens after in vivo experiments.

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“…At the same time, ZHN2 illustrates higher ZOI for both types of bacteria (Gram-positive and Gram-negative) compared to ZHN0, which can be attributed to the presence of some important phytocompounds of nimbolide, nimbidin, and 4 azadiradione-type limonoids. Previous researchers also exhibited evidence of higher ZOI, which was also correlated with the presence of various phytocompounds . Bacteriostatic activity also depends on various surface properties, such as surface roughness, surface charge, surface wettability, hydrodynamic forces, Brownian motion, and so on .…”

“…Previous researchers also exhibited evidence of higher ZOI, which was also correlated with the presence of various phytocompounds. 58 Bacteriostatic activity also depends on various surface properties, such as surface roughness, surface charge, surface wettability, hydrodynamic forces, Brownian motion, and so on. 59 Also, the surface roughness of the ZHN2 sample at the microscale level leads to fewer contact areas and increased cellular stress, indicating an increase in the antibacterial effect.…”

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“…McKay and Portnoy (35) also demonstrated that stationary-phase of bacteria is adequate phase for response to aminoglycosides. Dhanya et al (36) in a study on nimbolide from Azadirachta indica and its derivatives plus first-generation cephalosporin antibiotics described that significant reduction in the number of CFUs in the time kill assay was between 4 and 12 h. Also, in a study on the resistance of planktonic and biofilm cultures of Burkholde ria cepacia to ciprofloxacin and ceftazidime, Authors showed that during the exponential phase of bacterial growth up to the stationary phase, the resistance of bacteria decreased and antibacterial effect of these drugs increased. This may be due to availability and consumption rate of nutrient and oxygen and density of bacteria population (37).…”

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“…The highest inhibition level was found against K. pneumonia, as well as the synergistic action of nimbolide, when combined with the pre-existing antibiotics cephalexin (97% pure) and cefazolin (98% pure). Thus, a greater antimicrobial effect in the synergy with these antibiotics compared to the other tested compounds (such as deacetylnimbin) was shown [27].…”