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Phosphonamidates Integrating Sterically Hindered Phenols with Membrane-Active Cations: A Redox-Activated Approach to Antimicrobial Agents
(Multidisciplinary Digital Publishing Institute, 2026-05-18)
Elmira Gibadullina
;
Adel Shakirov
;
Margarita Neganova
;
Yulia Aleksandrova
;
Alexandra Voloshina
A strategy to create highly effective antimicrobial agents was proposed based on the conjugation of three functional components: a cationic quaternary ammonium salt (QAS) that exerts a membrane-disrupting effect and promotes selective accumulation on bacterial surfaces; a phosphonamidate linker for controlled activation; and a sterically hindered phenol (SHP) fragment as a potential redox component. This approach enabled the preparation of 40 target phosphonamidate–SHP/QAS hybrids in high yields (88–98%). Evaluation of their antimicrobial activity against major pathogens and methicillin-resistant Staphylococcus aureus (MRSA) revealed high potency against Gram-positive bacteria. The lead compounds achieved minimum inhibitory concentration (MIC) values of 0.7–2.8 μM, which is up to 10 times lower than that of the reference drug, norfloxacin. Mechanistic studies confirmed that these hybrids disrupt the bacterial membrane. In addition, an increase in intracellular ROS levels was observed for the most active compound. The SHP/QAS hybrids retained high activity against S. aureus ATCC 209P after 17 passages and showed low cytotoxicity (SI = 62–92) and negligible hemolysis. These properties indicate that this approach may offer a useful strategy for developing antibacterial agents with a potentially lower risk of inducing conventional resistance mechanisms.
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Iodine-Based Coordination Compounds: A Strategy Toward Antibiotic Potentiation
(Multidisciplinary Digital Publishing Institute, 2026-05-12)
Daniil Shepilov
;
Dana A. Askarova
;
Anar Seisembekova
;
Seitzhan Turganbay
;
Ardak B. Jumagaziyeva
Due to the increasing threat of antibiotic resistance and the emergence of new pathogenic strains, the development of effective combined therapeutic agents represents a crucial direction in the fight against infections. Within this study, several compounds were synthesized in which iodine is present in a coordination complex with antibiotics—sodium sulfadimidine and gentamicin sulfate. The physicochemical parameters of these compounds were investigated using capillary electrophoresis and UV spectroscopy, along with their cytotoxicity, antimicrobial, and antiviral activities. As a result of this work, two stable compounds, KC-246 and KC-248, were synthesized, demonstrating virus-inhibitory activity against herpes simplex virus and influenza A under extremely low cytotoxicity levels of 0.018–0.106 mg/mL. Additionally, they exhibited antimicrobial activity against representatives of the families Staphylococcaceae, Pseudomonadaceae, Enterobacteriaceae, Enterococcaceae, and yeast-like fungi. The minimum bactericidal concentrations (MBCs) ranged from 0.794 µg/mL to 0.198 µg/mL (KC-246) and from 2.093 µg/mL to 0.523 µg/mL (KC-248).
Цитирования (OpenAlex) 2
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Quantum Chemical Insights into Antibiotic Structure-Activity Relationships and Mechanisms of Action: A Review
(Multidisciplinary Digital Publishing Institute, 2026-07-17)
Seitzhan Turganbay
;
Alexander Ilin
;
Aitugan Sabitov
;
Jingcheng Hao
;
Anar Seisembekova
This review examines recent quantum chemical methodologies applied to investigating antibiotic structure and mechanisms of action. The discussion is organised into three sections: (1) enzymatic hydrolysis of the β-lactam ring, (2) interactions of antibiotics with ribosomal subunits and enzyme active sites, and (3) complex formation with metal ions. Each section evaluates how quantum chemical approaches, particularly density functional theory (DFT) and hybrid QM/MM techniques, model molecular processes relevant to antibiotic function, including transition states, electron density analyses, and metal coordination effects on antibacterial activity. Selected studies demonstrate the utility of these methodologies in interpreting experimental data and predicting physicochemical and biological properties of novel compounds. Distinct from previous literature, this review provides a comparative and up-to-date synthesis of quantum chemical methods related to enzymatic mechanisms and metal-based antibiotic systems, emphasising experimental validation strategies and practical guidelines for method selection in antibiotic research. It also identifies areas where quantum chemical modelling can integrate with experimental pharmacology and structural biology to support the rational design of next-generation antimicrobial agents. The review concludes by advocating an interdisciplinary framework combining quantum chemistry, biochemistry, and pharmacology to address antibiotic resistance. The review focuses primarily on antibiotics targeting bacterial cell wall and protein synthesis, particularly β-lactam antibiotics, ribosome-targeting agents, and their interactions with metal ions. Computational methods discussed are mainly limited to DFT, ab initio, and hybrid QM/MM approaches. It does not cover membrane-disrupting antibiotics, antiviral or antifungal agents, machine learning-based prediction methods, or purely molecular dynamics approaches outside a quantum mechanical context.
Цитирования (OpenAlex) 1

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