Pharmacological potential of the marine peptide cyclo(L-phenylalanyl-L-prolyl) against both multidrug-resistant, gram-negative Acinetobacter baumannii and gram-positive Staphylococcus aureus: structure – activity relationship, computational and experimental studies
The experimental and computational findings suggest that cFP is a promising antimicrobial lead and warrant further mechanistic and translational investigation.
Molecular docking results provided a molecular basis for the conjugate's interaction with target proteins (PDB IDs: 4LFU and 4TQX), suggesting its potential as a quorum-sensing modulator.
A series of novel haloarene-decorated tetrahydropyridine derivatives B(1a–1f) were synthesized via a simple, environmentally benign one-pot multicomponent reaction employing ethanol as a green solvent and [Et₃NH][HSO₄] as a Brønsted acid ionic liquid catalyst. The reaction utilized methyl acetoacetate (1 mmol), substituted aromatic aldehydes (2 mmol), and substituted anilines (2 mmol) at 60 °C to afford the desired compounds. All compounds were evaluated for their in vitro antimicrobial activity against three fungal strains (Candida albicans, Aspergillus niger, and Aspergillus clavatus), two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and two Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes), using the serial broth dilution method. Additionally, their antimalarial potential was assessed against chloroquine- and quinine-sensitive 3D7 and multidrug-resistant Dd2 strains of Plasmodium falciparum. Among the synthesized derivatives, compounds B1a, B1b, and B1b exhibited the most potent antimicrobial and antimalarial activities. Molecular docking studies revealed that compound B1f showed the highest binding affinity toward S. aureus nucleoside diphosphate kinase, with a predicted free binding energy of − 913 kcal/mol. Pharmacological profiling suggested favorable drug-like properties and non-toxic behavior. These findings highlight haloarene-decorated tetrahydropyridine derivatives as promising dual-action candidates with potential to combat both bacterial and malarial infections.
Bhavesh S. Hirani, Mohammad Murwih Alidmat, L. Hasoun et al.· Scientific Reports· 0 citations
The antibacterial activities of numerous medium and long-chain unsaturated fatty acids are well documented. However, the natural short-chain unsaturated fatty acid, 4-pentenoic acid (C5:1 Δ4) has not been systematically evaluated for its antibacterial activity, mechanism of action, or application potential. This study investigated these to provide a basis for novel preservatives. 4-Pentenoic acid showed broad-spectrum activity against 21 strains of pathogenic bacteria, with MICs 1.5-3 mg/mL, MBCs 3-6 mg/mL, and low resistance risk. It disrupted bacterial membrane integrity, inhibited biofilm formation, and regulated the pdu, nar and RND efflux pump genes, thereby affecting bacterial metabolism and stress responses. Checkerboard broth microdilution susceptibility assays confirmed that the combination of 4-pentenoic acid with antibiotics (such as meropenem) exerted additive antibacterial effects. At effective antibacterial concentrations, oral administration of 4-pentenoic acid caused no observable toxicity. It can markedly inhibit the proliferation of pathogenic bacteria in milk, beef, and peanut butter, while dosages close to the minimum inhibitory concentration exerted minimal adverse effects on the sensory properties and pH of these foods. In summary, this study provides theoretical and experimental basis for the development of new food preservatives and antibacterial agents.
Jiaming Mu, Jie Li, Fushuang Duan et al.· Journal of food microbiology· 0 citations
Chalcone‐sulfonamide hybrids (12a–h) were synthesized via Claisen–Schmidt condensation in good yields (64%–83%) and confirmed by NMR spectroscopy. The compounds exhibited moderate to good antibacterial activity against Gram‐negative (Escherichia coli, Pseudomonas aeruginosa) and Gram‐positive (Staphylococcus aureus, Streptococcus pyogenes) bacteria, with inhibition zones of up to 14.7 mm at 10 mg/mL, lower than that of sulfamethoxazole but comparable to that of related hybrids. DPPH antioxidant evaluation revealed IC50 values of 5.2–11.8 μg/mL, with compounds 12e and 12c exhibiting the highest activity. Additionally, compound 12e had the strongest protein denaturation inhibition (IC50 = 29.89 µg/mL), while 12g and 12h showed superior anti‐proteinase activity (IC50 = 115.6 and 112.2 µg/mL), outperforming diclofenac sodium. Molecular docking against DHPS (1AJ0, 1AD4), myeloperoxidase (1DNU), COX‐2 (5IKR), and topoisomerase IIα (4FM9) showed strong binding affinities (−8.3 to −10.3 kcal/mol), supported by key hydrogen–bonding and hydrophobic interactions. SwissADME and ProTox II analyses indicate favorable drug‐like properties, including Lipinski compliance, high GI absorption, no BBB penetration, and low predicted toxicity (LD50 > 6000 mg/kg). The hybrids presented here represent promising multifunctional leads with antibacterial, antioxidant, anti‐inflammatory, and drug‐like properties.
Mlis Belete, Endale Mulugeta, Daniel Rentsch et al.· ChemistryOpen· 0 citations
In an effort to diverge from the molecular framework of conventional drug molecules, a series of pyrrolo[3,4-d]isoxazolidine-naphthalimide hybrids have been synthesized via a 1,3-dipolar cycloaddition reaction between azomethine N-oxides and N-substituted maleimide, with the aim of exploring moieties capable of lessening bacterial infections that continue to burden human health and the livestock industry. Several of the synthesized analogues demonstrate potent antibacterial activity at low concentrations. Notably, 9k and 9l, featuring indole and N,N-dimethylaniline moieties, respectively, outperform chloramphenicol and amoxicillin against Staphylococcus aureus, as evidenced by their low MIC values (1.56 µg mL-1). Mechanistic studies reveal that both analogues effectively inhibit biofilm formation and disrupt bacterial cell membrane integrity, as confirmed by confocal laser scanning microscopy and SEM imaging, significantly reducing bacterial metabolic activity. These compounds also induce reactive oxygen species (ROS) generation and diminish cellular GSH activity, thereby weakening the bacterial antioxidant defense system and leading to oxidative damage and cell death. Additionally, these compounds show low cytotoxicity toward HEK293 cells, indicating good biocompatibility and a favorable safety profile. Both analogues exhibit strong affinity toward human serum albumin (HSA), as reflected by favorable binding constants, suggesting their potential suitability for transport in biological systems. This observation is further supported by molecular docking studies, which reveal stable binding orientations within the HSA binding cavity mediated by multiple non-covalent interactions. Furthermore, both analogues exhibit DNA intercalation behavior, which may hinder DNA replication and thereby contribute to bacterial cell death. Moreover, in silico ADME predictions indicate that the analogues possess a balanced drug-likeness profile, while quantum chemical calculations reveal a narrow HOMO-LUMO energy gap, suggesting enhanced electronic reactivity that may contribute to their antibacterial activity. Collectively, these findings highlight the potential of these multitarget antibacterial hybrids as promising leads for the development of new antibacterial agents against Staphylococcus aureus, a persistent threat to both human health and the livestock industry.
A. Jain, Kamaldeep Paul· Journal of materials chemist...· 0 citations
Background: Antimicrobial resistance (AMR) was directly attributable to an estimated 1.27 million deaths in 2019 and is projected to cause 1.91 million attributable deaths annually by 2050, creating sustained demand for antibacterial scaffolds that act through mechanisms distinct from conventional target inhibition. Anthraquinone–delocalised lipophilic cation (DLC) conjugates, in which a triphenylphosphonium (TPP⁺) or related cationic group drives electrostatic, membrane-targeted accumulation, are one such scaffold. SH1 (1-[(5-triphenylphosphonium-pentyl)oxy]anthraquinone) was previously synthesised and shown to accumulate selectively in the mitochondria of PC-3 prostate cancer cells, but its antibacterial activity has not previously been reported.
Aim: To our knowledge, following a structured search of PubMed and Scopus that identified no prior antibacterial data for this compound, this study presents the first antibacterial evaluation of SH1.
Methods: SH1 was assessed by broth microdilution in accordance with EUCAST guidelines against sensitive and drug-resistant strains of Staphylococcus aureus and Escherichia coli.
Results: SH1 demonstrated a minimum inhibitory concentration (MIC) of 1.6 mg/L against both antibiotic-sensitive (NCTC 6571) and methicillin-resistant (NCTC 13616) S. aureus, with a minimum bactericidal concentration (MBC) of 3.2 mg/L, indicating equipotent bactericidal activity against MRSA. Against E. coli (ATCC 47055, sensitive; LIB213, resistant), SH1 showed an MIC and MBC of 25.6 mg/L for both strains.
Conclusion: These results identify SH1 as a previously uncharacterised antibacterial agent active against MRSA and support the anthraquinone–DLC pharmacophore as a membrane-active scaffold warranting further structural optimisation. Halogenated analogues, including the arginine-conjugated derivative VO6 synthesised as part of this programme, remain candidates for future evaluation once solubility constraints are addressed. The study was limited to four bacterial strains, and comparator antibiotics were considered using published breakpoint data rather than side-by-side testing; these constraints are discussed further in the Limitations section.
Victor Arinze Orajekwe· Journal of applied chemical...· 0 citations
