Development of 4-[4-(Anilinomethyl)-3-phenyl-pyrazol-1-yl] Benzoic Acid Derivatives as Potent Anti-Staphylococci and Anti-Enterococci Agents

Abstract

From a library of compounds, 11 hit antibacterial agents have been identified as potent anti-Gram-positive bacterial agents. These pyrazole derivatives are active against two groups of pathogens, staphylococci and enterococci, with minimum inhibitory concentration (MIC) values as low as 0.78 μg/mL. These potent compounds showed bactericidal action, and some were effective at inhibiting and eradicating Staphylococcus aureus and Enterococcus faecalis biofilms. Real-time biofilm inhibition by the potent compounds was studied, by using Bioscreen C. These lead compounds were also very potent against S. aureus persisters as compared to controls, gentamycin and vancomycin. In multiple passage studies, bacteria developed little resistance to these compounds (no more than 2 × MIC). The plausible mode of action of the lead compounds is the permeabilization of the cell membrane determined by flow cytometry and protein leakage assays. With the detailed antimicrobial studies, both in planktonic and biofilm contexts, some of these potent compounds have the potential for further antimicrobial drug development.

Development and Antibacterial Properties of 4-[4-(Anilinomethyl)-3-phenylpyrazol-1-yl]benzoic Acid Derivatives as Fatty Acid Biosynthesis Inhibitors

“…2 Hz),151.1,149.4,142.8,134.1,131.6,131.0,130.3,130.1 ( 3 J C−F = 8.2 Hz), 129.4 ( 4 J C−F = 2.9 Hz), 128. 7, 119.1, 118.1, 117.2, 116.2 ( 2 J C−F = 21.7 Hz),113.1,112.5,39.0 = 8.7 Hz),129.4,129.2,128.7,124.9,119.4,118.2,116.2 ( 2 150.9, 148.3, 142.8, 135.7, 131.5, 130.0 ( 3 J C−F = 7.7 Hz),129.4,128.3,119.7,118.1,116.8,116.2 ( 2 J C−F = 21.2 Hz),112.2,79.8,79.5,79.1,38. 6 Hz),151.1,142.8,133.1,132.0,131.6,130.3,130.2,130.1( 3 = 8.2 Hz),129.4,128.7,118.2,116.1 ( 2 J C−F = 21.7 Hz),115.9,115.7 (11). White solid (373 mg, 82%); IR (KBr pellet, cm −1 ) 3081, 3059,3025,…”

“…Real-time monitoring of biofilm growth/inhibition was performed following the methodology reported earlier. 11 In brief, overnight bacterial culture (∼1 × 10 6 CFU/mL) in CAMHB containing 1% glucose was seeded into 100-well polystyrene honeycomb plates and incubated for 24 h at 37 °C to establish biofilm in the chamber of BioScreen C°Pro (Growth Curves USA, Piscataway, NJ, USA). Control wells received only medium as sterility control.…”

“…In 2019, S. aureus and MRSA caused more than 100 000 deaths worldwide. S. aureus causes the most common infections in humans occurring in both community-acquired and hospital-acquired settings. , Similarly, E. faecium causes a variety of problems including urinary tract, intra-abdominal, pelvic, and soft tissue infections, bacteremia, and endocarditis . Approximately 30% of all healthcare-associated enterococcal infections are due to vancomycin-resistant enterococci (VRE), and these strains are increasingly becoming resistant to other antibiotics.…”

Overcoming Barriers to Preventing and Treating P. aeruginosa Infections Using AAV Vectored Immunoprophylaxis

“…Carbapenem-resistant P. aeruginosa is among the group listed as priority 1, due to its ability to cause severe infection in nosocomial settings, which can lead to deadly infections including bacteremia and pneumonia [ 60 ]. Recently, P. aeruginosa has been listed as one of the six leading pathogens responsible for causes of AMR deaths, which have been termed ‘SPEAKS’—an acronym for Staphylococcus aureus , Pseudomonas aeruginosa , Escherichia coli , Acinetobacter baumannii , Klebsiella pneumonia and Streptococcous pneumoniae [ 59 , 61 ]. Various antibiotic survival mechanisms are utilized by P. aeruginosa to support the survival of persister cells, an antibiotic tolerant phenotype of bacteria, which serve to repopulate the bacterial population after the course of antibiotic treatment has been completed.…”

Synthetic Flavonoid BrCl-Flav—An Alternative Solution to Combat ESKAPE Pathogens

“…[ 7 ]. On the other hand, SPEAKS pathogens ( S. aureus , P. aeruginosa , Escherichia coli , A. baumannii , K. pneumoniae and S. pneumoniae ) are the leading causes of AMR deaths [ 8 ]. Most of them exhibit multidrug resistance (MDR), which is considered one of the greatest challenges in clinical practice [ 9 ].…”