Characterization of antimicrobial properties of pleurotus ostreatus-derived phenolic compounds: Implications for drug development against antibiotic-resistant neisseria gonorrhoeal isolates.

Abstract

The global spread of antimicrobial resistance in Neisseria gonorrhoeae presents a major challenge to treating gonorrhoeal infections, necessitating immediate intervention strategies. This study investigates the prevalence and mechanisms of antibiotic resistance in N. gonorrhoeae isolates from KwaZulu Natal, South Africa, where antimicrobial resistance monitoring is limited. Utilizing molecular and culture methods, significant resistance levels were detected: 48% of isolates were fully resistant to ciprofloxacin, 14% to both penicillin and tetracycline, and one isolate showed resistance to azithromycin, while ceftriaxone remained universally effective. The extracts exhibited varying antimicrobial activities against E. coli and S. aureus, with a mean extract concentration of 1x10-5 mg/mL. In contrast, N. gonorrhoeae isolates showed a mean MIC concentration of 1x10-3 mg/mL, indicating a higher resistance to the target extracts compared to E. coli and S. aureus. The high resistance to penicillin, with MICs exceeding 32 μg/mL, is attributed to the presence of penicillinase-producing plasmids and mutations in penicillin-binding proteins (PBPs), particularly in the penA gene. Logistic regression indicated a strong correlation between bacterial growth rates and tetracycline concentrations, emphasizing the complexity of resistance dynamics. The study also explored flavonoid compounds as alternative therapies, with quercetin showing notable antibacterial properties. Molecular docking and dynamics simulations were employed to examine quercetin's interaction with critical bacterial proteins, penicillin-binding protein 2 (PBP2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), essential for cell wall synthesis and metabolism. Quercetin demonstrated strong binding affinity to the active sites of these proteins, potentially inhibiting their function. Molecular dynamics (MD) simulations provided insights into the long-term stability and dynamic behaviour of the quercetin-protein complexes, showing consistent and secure binding within the active sites of PBP2 and GAPDH. Analysis of rootmean- square deviation (RMSD) and root-mean-square fluctuation (RMSF) confirmed the stability of these protein structures during simulation. Binding-free energy calculations using the molecular mechanics method confirmed quercetin's strong inhibitory potential against both PBP2 and GAPDH. Structural insights from Procheck and other computational tools identified crucial residues in the binding pockets, providing valuable information for developing more effective quercetin derivatives or other flavonoid-based therapeutics. This comprehensive study underscores quercetin as a promising alternative treatment for drugresistant N. gonorrhoeae and emphasizes the need for continued exploration of flavonoid compounds in combating antimicrobial resistance. The findings advocate for a global collaborative effort to combat antimicrobial resistance in N. gonorrhoeae, involving robust surveillance systems, advanced molecular techniques, and novel antimicrobial agents to curb the spread of resistant strains,ensure effective treatment, and safeguard public health.