Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm

Abstract

Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1–8 μg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-α and IL-6 release and increase in IL-1β. These data provide evidence that MenA inhibitors act as TNF-α and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents.

Novel Miniature Membrane Active Lipopeptidomimetics against Planktonic and Biofilm Embedded Methicillin-Resistant Staphylococcus aureus

“…Along with slow growth under nutrient depletion conditions, biofilm-associated infections are complicated by the presence of extracellular polymeric substance (EPS) matrix which provides a physical barrier and allows bacterial populations to adhere together 7 . For a number of antibiotics and synthetic molecules, much higher concentrations have been reported to be effective towards eradication of biofilms 5 , 10 , 24 , 60 , 61 while sub-lethal concentrations of many antibiotics such as VAN and OXA are even known to promote staphylococcal biofilm formation on surfaces 62 . To evaluate the efficacy of designed peptidomimetics we next developed a 24 h biofilm formation inhibition model in a 96-well plate.…”

Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway

“…The glyoxalase pathway is a promising drug target for neurodegenerative diseases. Drug discovery [4] , [140] , [141] , [142] , [143] , [144] and delivery [145] , [146] , [147] processes could be explored in this target against neurodegenerative diseases. Novel flavonoids could be designed, synthesized, and tested to protect neurodegenerative diseases through glyoxalase pathway.…”

Iron/Heme Metabolism-Targeted Gallium(III) Nanoparticles Are Active against Extracellular and Intracellular Pseudomonas aeruginosa and Acinetobacter baumannii

“…Biofilms are responsible for tolerance and resistance to antibiotics, thereby increasing the importance of developing novel antibiofilm therapies. To determine the effect of GaPP and its nanoparticles (FGaPP and CDGaPP) against biofilms of both bacterial species, biofilms grown on plasma-coated wells were treated with 5ϫ the MIC (40 g/ml) in iron-depleted medium (30). The tetracycline antibiotic minocycline was used as a positive control for antibiofilm activity for comparison with gallium compounds.…”