Jean Michel Brunel

This review highlights the chemistry and therapeutic potential of the shark‐derived aminosterols squalamine and trodusquemine. It surveys the evolution of synthetic strategies developed to access these structurally unique natural products, with emphasis on stereoselective and more efficient routes to squalamine. It also examines their broad spectrum of biological activities, including antiangiogenic, antimicrobial, antiparasitic and antiviral effects, together with the anti‐obesity properties of trodusquemine and the emerging interest of both aminosterols in neurodegenerative disorders. Altogether, these studies position aminosterols as promising membrane‐active scaffolds for future drug discovery, even though no compound from this class has yet reached the market.

The rise of multidrug-resistant Gram-negative bacteria has increased interest in non-antibiotic adjuvants able to restore antibiotic efficacy. In this study, nineteen dexibuprofen-polyamine conjugates were synthesized, combining a hydrophobic ibuprofen moiety with a protonatable polyamine chain. Their intrinsic antibacterial activity and ability to potentiate doxycycline were evaluated. Most compounds showed limited activity, revealing a clear structure-activity relationship in which longer polyamine chains were required. The spermine conjugate 15 was the most active S-series derivative, while inversion of the ibuprofen stereocenter produced compound 20 with improved activity. At 10 µM, compound 20 reduced the MICs of several antibiotics against Escherichia coli AG100 and multidrug-resistant AG102, although the effect varied with the antibiotic and strain. Mechanistic assays indicated that compound 20 was neither a strong outer-membrane permeabilizer nor a membrane-depolarizing agent, suggesting a more subtle mechanism of antibiotic potentiation that warrants further investigation. These results support spermine–ibuprofen conjugates as promising antibacterial adjuvant chemotypes.

The increasing prevalence of multidrug-resistant Gram-negative bacteria has renewed interest in non-antibiotic adjuvants that can restore the activity of existing antibacterial agents. Here, we designed a focused series of ibuprofen-polyamine conjugates in which the ibuprofen moiety provides a compact hydrophobic anchor and the polyamine chain provides a protonatable cationic domain, thereby generating amphiphilic molecules related in concept to previously described polyamine-containing antibiotic enhancers. Nineteen derivatives of dexibuprofen were synthesized and evaluated for intrinsic antibacterial activity and for their ability to potentiate doxycycline. Most derivatives were poorly active, defining a clear structure-activity relationship in which extended polyamine chains were required for activity. The spermine conjugate 15 was the most active S-series compound, and inversion of the ibuprofen stereocenter afforded compound 20, which displayed improved antibacterial activity. At 10 µM, compound 20 reduced the MICs of several antibiotics against Escherichia coli AG100 and multidrug-resistant AG102, with potentiation depending on both the antibiotic and bacterial strain. Nitrocefin hydrolysis and DiSC3(5) assays showed that compound 20 did not behave as a strong outer-membrane permeabilizer or membrane-depolarizing agent under the conditions tested. These data identify spermine-ibuprofen conjugates as a tractable adjuvant chemotype while indicating that the mechanism of potentiation is more subtle than gross membrane disruption and requires further investigation.

Because fungal diseases are among the major constraints affecting modern agriculture, there is an urgent need to identify new, effective, and environmentally sustainable alternatives for crop protection. As part of our ongoing studies on propolis, we investigated the potential of natural bee-collected compounds to act against phytopathogenic fungi. In vitro evidence suggests that pinocembrin isolated from Romanian propolis exhibits antifungal activity and may effectively control the growth of several phytopathogenic fungi, including F. oxysporum , B. cinerea , and Z. tritici , thereby supporting the phyto-pharmaceutical potential of propolis as an ecological alternative for crop management in sustainable agriculture.

The marine environment represents a rich source of novel antimicrobial compounds. This study investigated the isolation and synthesis of antimicrobial agents from the New Zealand ascidian Pseudodistoma opacum to identify natural products and derivatives with potential pharmacological applications. Screening of a marine natural product library and related synthetic analogues revealed several compounds exhibiting antibiotic-potentiating activity in combination with doxycycline against Pseudomonas aeruginosa. To further explore these findings, the most active natural product, opacaline A (1), was synthesized, and a structure–activity relationship (SAR) study was conducted to identify key structural features required for activity. This work reports the first total synthesis of opacaline A (1) and racemic 7-bromohomotrypargine (3). Biological evaluation demonstrated that the presence of a bromine substituent and a free amine or guanidine group is essential for both intrinsic antimicrobial activity and antibiotic potentiation. Additionally, both oxidation states of the β-carboline ring (aromatic and tetrahydro-) were found to retain activity. These findings provide insight into the structural requirements for activity and support further development of these compounds as antimicrobial adjuvants.

Overexpression of the NorA efflux pump is a principal mechanism by which Staphylococcus aureus pumps out fluoroquinolone antibiotics. Therefore, making efflux pump inhibitors (EPIs) is a compelling strategy to restore antibiotic efficacy. Sulphur containing heterocycles and peptidomimetic scaffolds such as Phe-Arg-β-naphthylamide (PAβN) have independently demonstrated NorA EPI activity, yet their clinical translation has been hampered by cytotoxicity at active concentrations. To merge these two chemotypes, herein we report the design and synthesis of three peptidomimetic libraries containing thiophene-3-carboxylic acyl (I), 3-(methylthio)propanoic acyl (II) and 3-(methylsulfinyl)propanoic acyl (III) moieties to investigate the contribution of ring rigidity, aromaticity and sulphur oxidation state to EPI potency. Using fluorescence-based ethidium bromide (EtBr) accumulation assay, broth microdilution and checkerboard assays, we assessed 42 sulphur peptidomimetics for their ability to inhibit NorA efflux pump in S. aureus. Lead compounds 3f and 3g demonstrated potent EPI activity in a NorA overexpressing S. aureus strain and checkerboard assays showed synergistic/additive effects in combination with ciprofloxacin and norfloxacin resulting in meaningful reductions of minimal inhibitory concentration (MIC). Furthermore, molecular docking was used to determine the most favourable interactions and binding pose. Systematic structure-activity relationship (SAR) analysis and molecular docking study revealed that the rigid thiophene ring and 4-methoxy benzyl isocyanide component are both critical determinants of the inhibitory activity. Replacement of these fragments or oxidized sulfinyl analogues led to significant loss of potency. Crucially, both compounds exhibited no cytotoxicity toward healthy human cells up to 200 μM, overcoming the key limitation of existing EPIs. In general, these results uphold the idea that rationally designed peptidomimetic frameworks can act as competitive inhibitors of bacterial efflux pumps and may work as potential antibiotic adjuvants to reduce efflux-driven resistance.

Staphylococcus aureus is a Gram-positive opportunistic pathogen and a top priority bacterium in the fight against antimicrobial resistance. Its high propensity to develop resistance, its high virulence, and its ability to form biofilms and persist intracellularly result in difficult-to-treat infections against, which new chemical classes are urgently needed. Here, we investigated the antibacterial activity of oxadiazolone-core derivatives (OX) against planktonic, intracellular, and biofilm-associated S. aureus. Among the tested compounds, MpPPOX exhibited a bactericidal effect on extracellular bacteria with an MIC similar to that of vancomycin; iBPOX mainly inhibited intracellular replication, while HPOX strongly impaired initial biofilm formation. These results prompted us to identify the potential target enzymes of the three OXs via activity-based protein profiling, combined with mass spectrometry. The antibiofilm HPOX compound was indeed found to primarily react with enzymes involved in biofilm formation and associated virulence, while iBPOX and the most active MpPPOX inhibitor targeted multiple (Ser/Cys)-based enzymes. Among these, the FabH protein has been confirmed as a vulnerable target of MpPPOX. Overall, this study underscores the multitarget nature of the OXs, which covalently bind to several (Ser/Cys)-based enzymes of interest. Such property makes them highly versatile chemotypes that could be used as broad-spectrum antimicrobial agents, notably by improving the antibiofilm activity of ineffective or poorly active drugs.

Antimicrobial resistance is a serious global public health concern, with Acinetobacter baumannii recognized as one of the most problematic multidrug-resistant (MDR) pathogens. This Gram-negative bacterium is highly persistent in the environment, possesses a remarkably adaptable cell envelope, and forms biofilms. As the effectiveness of conventional antibiotics declines, alternative strategies are being actively explored, particularly membrane-targeting approaches based on synthetic copolymers. These compounds mimic antimicrobial peptides, offer enhanced stability and structural tunability, and have a lower propensity to develop resistance. Recent advances in polymer chemistry have led to the design of antibacterial polymers with activity against MDR A. baumannii. Some of these act synergistically with existing antibiotics, restoring bacterial susceptibility or disrupting biofilms. However, their non-degradability remains a concern due to its potential implications for body/environment accumulation and related toxicity and/or selection of resistant strains. This review examines the biology of the A. baumannii cell envelope, its resistance mechanisms, and treatment limitations, while emphasizing the promise of membrane-active copolymers. By bridging materials science and microbiology, these approaches offer promising strategies for combating World Health Organization priority pathogens.

The development of new antibiotics has been recognized for over two decades as a major challenge in combating multidrug-resistant bacteria. Herein, we report the synthesis and QSAR studies of claramine derivatives, a new class of broad-spectrum antimicrobial agents active against both susceptible and resistant Gram-positive and Gram-negative strains. The observed antimicrobial activities were rationalized based on key topological parameters of the derivatives, while cytotoxicity was interpreted by correlating half maximal inhibitory concentration (IC₅₀) values with QSAR models. Owing to the low cytotoxicity observed for several analogues, this molecular class represents a promising alternative for the development of novel agents to counteract multidrug resistance.