There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure–activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.

The quorum sensing (QS) system in multi-drug-resistant bacteria such as P. aeruginosa is primarily responsible for the development of antibiotic resistance and is considered an attractive target for antimicrobial drug discovery. In this study, we synthesised a series of novel selenourea and thiourea-containing dihydropyrrol-2-one (DHP) analogues as LasR antagonists. The selenium DHP derivatives displayed significantly better quorum-sensing inhibition (QSI) activities than the corresponding sulphur analogues. The most potent analogue 3e efficiently inhibited the las QS system by 81% at 125 µM and 53% at 31 µM. Additionally, all the compounds were screened for their minimum inhibitory concentration (MIC) against the Gram-positive bacterium S. aureus, and interestingly, only the selenium analogues showed antibacterial activity, with 3c and 3e being the most potent with a MIC of 15.6 µM.

There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.

As bacteria continue to develop resistance mechanisms against antimicrobials, an alternative method to tackle this global concern must be developed. As the pqs system is the most well-known and responsible for biofilm and pyocyanin production, quinazolinone inhibitors of the pqs system in P. aeruginosa were developed. Molecular docking following a rationalised medicinal chemistry approach was adopted to design these analogues. An analysis of docking data suggested that compound 6b could bind with the key residues in the ligand binding domain of PqsR in a similar fashion to the known antagonist M64. The modification of cyclic groups at the 3-position of the quinazolinone core, the introduction of a halogen at the aromatic core and the modification of the terminal group with aromatic and aliphatic chains were investigated to guide the synthesis of a library of 16 quinazolinone analogues. All quinazolinone analogues were tested in vitro for pqs inhibition, with the most active compounds 6b and 6e being tested for biofilm and growth inhibition in P. aeruginosa (PAO1). Compound 6b displayed the highest pqs inhibitory activity (73.4%, 72.1% and 53.7% at 100, 50 and 25 µM, respectively) with no bacterial growth inhibition. However, compounds 6b and 6e only inhibited biofilm formation by 10% and 5%, respectively.

Nano zero-valent metals (nZVMs) have been extensively utilized for decades in the reductive remediation of groundwater contaminated with chlorinated organic compounds, owing to their robust reducing capabilities, simple application, and cost-effectiveness. Nevertheless, there remains a dearth of information regarding the efficient reductive defluorination of linear or branched per- and polyfluoroalkyl substances (PFASs) using nZVMs as reductants, largely due to the absence of appropriate catalysts. In this work, various soluble porphyrin ligands [[meso‑tetra(4-carboxyphenyl)porphyrinato]cobalt(III)]Cl·7H₂O (CoTCPP), [[meso‑tetra(4-sulfonatophenyl) porphyrinato]cobalt(III)]·9H₂O (CoTPPS), and [[meso‑tetra(4-N-methylpyridyl) porphyrinato]cobalt(II)](I)₄·4H₂O (CoTMpyP) have been explored for defluorination of PFASs in the presence of the nZn⁰ as reductant. Among these, the cationic CoTMpyP showed best defluorination efficiencies for br-perfluorooctane sulfonate (PFOS) (94%), br-perfluorooctanoic acid (PFOA) (89%), and 3,7-Perfluorodecanoic acid (PFDA) (60%) after 1 day at 70 °C. The defluorination rate constant of this system (CoTMpyP-nZn⁰) is 88-164 times higher than the VB₁₂-nZn⁰ system for the investigated br-PFASs. The CoTMpyP-nZn⁰ also performed effectively at room temperature (55% for br-PFOS, 55% for br-PFOA and 25% for 3,7-PFDA after 1day), demonstrating the great potential of in-situ application. The effect of various solubilizing substituents, electron transfer flow and corresponding PFASs defluorination pathways in the CoTMpyP-nZn⁰ system were investigated by both experiments and density functional theory (DFT) calculations. SYNOPSIS: Due to the unavailability of active catalysts, available information on reductive remediation of PFAS by zero-valent metals (ZVMs) is still inadequate. This study explores the effective defluorination of various branched PFASs using soluble porphyrin-ZVM systems and offers a systematic approach for designing the next generation of catalysts for PFAS remediation.