N-Acetylcysteine as a Bacterial Antibiofilm Adjuvant: Mechanisms, Synergistic Combinations and Clinical Translation

Synergistic bactericidal mechanism of carvacrol and ε-polylysine against Staphylococcus aureus: dysregulation of cellular homeostasis and metabolism

This study for the first time constructs a complete temporal mechanism chain from initial membrane damage and rapid metabolic disorder to downstream cellular dysfunction for the CAR-ε-PL synergy, providing a novel theoretical basis for developing natural antimicrobial strategies in food preservation.

Rational N-Terminal Tuning of Bacitracin A: Repurposing a Classic Antibiotic to Combat Multidrug-Resistant Gram-Positive Pathogens

The increasing threat of infections caused by multidrug-resistant Gram-positive pathogens such as MRSA and VRE has driven the structural remodeling and repurposing of traditional antibiotics as a key strategy to combat bacterial resistance. Herein, using bacitracin A as a lead template, we established a site-selective semisynthetic modification strategy via reductive amination of its N-terminal primary amine. 32 derivatives were designed and synthesized, and their structure–activity relationships were systematically evaluated. Optimized derivatives exhibited potent activity against MRSA and VRE, with 4–32-fold enhanced antibacterial potency compared with bacitracin A, together with improved bactericidal properties, safety profiles, and pharmacokinetic characteristics. Mechanistically, hydrophobic N-terminal modification endows bacitracin A with multiple antibacterial modes, including enhanced inhibition of cell wall peptidoglycan biosynthesis, obvious membrane depolarization, and disruption of the purine metabolic pathway. These findings provide a rational strategy for bacitracin optimization and highlight the potential of N-terminal modification for developing improved antibacterial agents.

A Comprehensive Review of Natural and Synthetic Flavonoids as Antibiofilm Agents Against Bacterial Biofilms

Dihalogenated indoles with antimicrobial activity against C. acnes and polymicrobial biofilms.

Acne vulgaris is a chronic inflammatory skin disorder in which Cutibacterium acnes contributes to disease persistence through biofilm formation, lipid metabolism, and production of inflammatory metabolites within the pilosebaceous unit. Targeting bacterial physiological pathways that sustain these processes represents a potential therapeutic strategy beyond conventional antibiotic approaches. In this study, we evaluated a panel of halogenated indole derivatives and identified 6-bromo-4-iodoindole as a potent inhibitor of C. acnes growth and biofilm formation. The compound exhibited a minimum inhibitory concentration of 20 μg/mL and disrupted biofilm architecture. Further analyses revealed that treatment markedly altered several virulence-associated phenotypes, including reductions in extracellular lipase activity, cell-surface hydrophobicity, extracellular polymeric substance production, and porphyrin levels, accompanied by increased intracellular reactive oxygen species. Because lipase activity plays a central role in sebum metabolism and follicular colonization by C. acnes, molecular docking was performed to evaluate potential target engagement. Docking simulations suggested that 6-bromo-4-iodoindole occupies the catalytic pocket of C. acnes triacylglycerol lipase, providing a structural basis for the observed suppression of lipase-dependent phenotypes. Importantly, the compound retained biofilm inhibitory activity in polymicrobial C. acnes + Staphylococcus aureus biofilms, exhibited broad-spectrum growth inhibition extending to S. epidermidis, and significantly reduced bacterial recovery in an ex vivo porcine skin model. In silico pharmacokinetic analyses further indicated physicochemical properties compatible with localized topical delivery. Together, these findings demonstrate that a dihalogenated indole reduces lipase-associated virulence related phenotypes in C. acnes and suppresses biofilm formation in skin-relevant environments, supporting further investigation of this scaffold as a therapeutic strategy targeting acne-associated microbial physiology.

Lauric Acid- and BDSF-Derived N-Acyl Sulfonamides as Potent Antibiofilm and Antivirulence Agents against Staphylococcus aureus.

Biofilm-associated Staphylococcus aureus infections remain difficult to treat using conventional antibiotics. Herein, we report the synthesis and biological evaluation of lauric acid- and BDSF-derived N-acyl sulfonamides as antibiofilm and antivirulence agents. Structure-activity relationship (SAR) analysis identified 4-tert-butylphenyl sulfonyldodecenamide (59) as a lead compound with a minimum inhibitory concentration of 5 μg/mL and >60% inhibition of MSSA and MRSA biofilm formation at sub-minimum inhibitory concentration levels. Microscopy confirmed marked reductions in biofilm biomass and thickness. The lead compound synergized with gentamicin and tobramycin, suppressed hemolysis, slime production, metabolic activity, and cell-surface hydrophobicity, and induced intracellular reactive oxygen species. qRT-PCR revealed downregulation of key virulence regulators (agrA, RNAIII, saeR, and seb), indicating disruption of quorum-sensing circuitry. SAR modeling rationalized steric and electronic requirements for activity. Low toxicity in plant, nematode, and mammalian models highlights bioisosteric N-acyl sulfonamides as promising antivirulence scaffolds for combating S. aureus biofilm infections.

L-Serine potentiates the efficacy of Isoniazid, and Rifampicin as host-directed adjunctive treatment for Mycobacterium tuberculosis

L-Serine is an important metabolic and immunomodulatory biomolecule with promising role in managing infections, and autoimmune diseases. L-Serine provides the energy requirements and triggers the toll-like receptor signalling collaterally. However, the role of L-Serine in host antimicrobial response against Mycobacterium tuberculosis (M.tb) remains unexplored. In this study, we investigated whether this metabolite could modulate the antibiotics efficacy against M.tb. Although L-Serine exhibits limited intrinsic anti-mycobacterial activity, but L-Serine demonstrates a synergistic effect when combined with rifampicin and moxifloxacin against both drug-sensitive and multidrug-resistant M.tb. Moreover, L-Serine particularly in combination with palmitic acid showed the enhanced intracellular bacterial clearance in a dose- and time-dependent manner in murine and human macrophages. This synergistic effect was accompanied by increased nitric oxide production and modulation of the host immune response. We identified elevated levels of pro-inflammatory cytokines and reduced IL-10 expression. Furthermore, the metabolic supplementation demonstrated enhanced antimicrobial activity in isolated primary CD14⁺ monocytes from TB patients. Similarly, the metabolic supplementation of L-Serine in combination with isoniazid and rifampicin significantly reduced bacterial burdens in the lungs and spleen, while improving tissue architecture in murine infection model. Our observations suggest that L-Serine contributes to the observed therapeutic effects. Collectively, this study concludes that L-Serine acts as a promising host-directed therapeutic adjunct, which enhances antimicrobial immunity and potentiating antibiotic efficacy, providing a potential strategy for improving tuberculosis treatment outcomes.