Phytochemical Profiling and Antibacterial Activity of Moroccan Monofloral Honeys Against Multidrug-Resistant Uropathogens: In Vitro, ADMET, Molecular Docking, and Molecular Dynamics Approaches.

Urinary tract infections represent a significant public health issue exacerbated by bacterial antibiotic resistance. Honey, due to its phenolic compounds, offers a promising natural alternative. This study explores the phenolic profile of monofloral honeys from the Beni Mellal-Khenifra region and their antibacterial activity against multidrug-resistant strains. Four monofloral honeys from Beni Mellal-Khenifra were analyzed for their phenolic composition and evaluated for antibacterial activity against multidrug-resistant uropathogenic bacteria. Computational studies were also performed to explore the potential mechanisms of action of the identified compounds. HPLC-UV detection identified distinct phenolic profiles in four monofloral honeys. Carob honey showed the highest diversity, with eight compounds identified, notably myricetin (63.99 μg/mg), trans-ferulic acid (33.99 μg/mg), gallic acid (21.02 μg/mg), naringin (17.95 μg/mg), catechin (3.66 μg/mg), and trans-cinnamic acid (2.75 μg/mg). Euphorbia honey was rich in hydroxycinnamic acids, especially caffeic acid (285.35 μg/mg), p-coumaric acid (190.93 μg/mg), and trans-ferulic acid (125.37 μg/mg). Anise honey contained high levels of naringin (669.84 μg/mg), along with myricetin (90.08 μg/mg) and 3-hydroxybenzoic acid (76.59 μg/mg). In contrast, citrus honey exhibited the lowest polyphenolic content, with only gallic acid (0.21 μg/mg) and catechin (2.69 μg/mg) detected. The honey samples exhibited notable antibacterial activity against multidrug-resistant uropathogenic bacteria, including E. coli, K. pneumoniae, and S. aureus. Among them, euphorbia and carob honeys demonstrated the highest antibacterial efficacy, with MBC values of 25% (v/v) against S. aureus and 50% against E. coli and K. pneumoniae. In contrast, citrus and anise honeys showed lower bactericidal activity, with MBC values reaching 75% (v/v) for E. coli and K. pneumoniae, and 50% for S. aureus. In silico, analyses showed that kaempferol, quercetin, catechin, and myricetin exhibit high binding affinities (up to -8.3 kcal/mol) against major bacterial targets. Molecular dynamics confirmed the stability of the quercetin-GyrB complex (RMSD ~0.35 nm). ADMET and toxicity profiles identified catechin and 3-hydroxybenzoic acid as the most promising candidates, combining good intestinal absorption, low predicted toxicity (LD50≈10,000 mg/kg), and favorable pharmacokinetics. These findings confirm the important role of honey's phenolic compounds in inhibiting multidrug-resistant bacteria. Future research should focus on in vivo validation and the formulation of effective therapeutic products based on these honeys.