Frank Schweizer

This study reports the synthesis, cytotoxic evaluation, and mechanistic insights of an amphiphilic triamino glycosylated antitumor ether lipid (GAEL). A series of aryl-substituted tricationic d-galacto-GAELs were synthesized to mimic cationic amphiphilic drug (CAD)-like structural characteristics. Among the series, the quinoline-bearing triamino GAEL (compound 17) exhibited the highest cytotoxicity in 2D cultures against drug-sensitive and drug-resistant ovarian, breast, pancreatic, liver, prostate, and brain cancer cells, completely eliminating all cells, whereas cisplatin and doxorubicin were less effective. GAEL 17 also demonstrated superior efficacy in an SK-OV-3 3D tumor spheroid model, fully disintegrating spheroids and inducing cell death at concentrations ≥25 μM. In contrast, doxorubicin reduced viability but did not eradicate spheroids at 50 μM, likely due to slower drug action or limited penetration over 48 h exposure. GAEL 17 retained caspase-independent, non-apoptotic cell death. LysoTracker assay indicated lysosomal disruption, while LipidTOX staining showed dose-dependent fluorescence, consistent with CAD-like lipid accumulation.

The widespread emergence of multidrug-resistant (MDR) Gram-negative bacteria prompted the reintroduction of polymyxins in the clinic despite their adverse effects. Ongoing research is primarily focused on the development of non-nephrotoxic and -neurotoxic polymyxins as not only standalone agents but also as potentiators that enhance the activity of a partner antibiotic. Safer derivatives of polymyxin B ₃ , a minor component of polymyxin B, were synthesized and utilized as a potentiator of multiple antibiotics. Compound 1 , consisting of Dap residues, was nontoxic to kidney cells and is a promising outer membrane permeabilizer that synergized with six different classes of antibiotics against MDR Gram-negative bacteria. Compound 1 extended the activity spectrum of rifampicin, zoliflodacin, and pristinamycin by lowering the minimum inhibitory concentrations of these antibiotics below their interpretative susceptibility breakpoints in MDR Pseudomonas aeruginosa , Acinetobacter baumannii , Escherichia coli , Klebsiella pneumoniae , and Enterobacter cloacae . Notably, the novel combination of zoliflodacin, a first-in-class antibiotic in phase III trials for gonorrhea, and compound 1 exhibited potent bactericidal activity in MDR P. aeruginosa and A. baumannii .

The prevalence of antimicrobial resistance (AMR) necessitates the development of alternative therapeutic options, particularly against critical priority Gram-negative pathogens. The utilization of antibiotic adjuvants or potentiators is an advantageous strategy that targets bacterial resistance mechanisms, thereby augmenting the activity of an antibiotic used in combination. Among these, outer membrane (OM) permeabilizers are a promising class of adjuvants which compromise the OM barrier unique to Gram-negative bacteria. This review focuses on the emerging role of polymyxins and aminoglycosides – two structurally distinct antibiotics with different modes of action, but share the ability to interact with the bacterial OM. Here, we explore the design, modification, and application of polymyxin- and aminoglycoside-based OM permeabilizers, highlighting their potential against resistant Gram-negative infections.

Cefepime–taniborbactam (FEP–TAN) and meropenem–xeruborbactam (MEM–XER) are β-lactam–β-lactamase inhibitor (BL–BLI) combinations currently in development and both projected to treat metallo-β-lactamase (MBL)-producing Gram-negative pathogens. Among Gram-negative pathogens, the low permeability of the outer membrane of Pseudomonas aeruginosa poses unique challenges to drug discovery in general and to BL–BLIs in particular. This study set out to augment β-lactam antibiotic potency by enhancing outer membrane permeability of P. aeruginosa using novel amphiphilic aminoglycoside-based outer membrane permeabilizers. Amphiphilic nebramines acting as outer membrane permeabilizers, were synthesized and evaluated in combination with β-lactam antibiotics and BL–BLIs against P. aeruginosa clinical isolates harbouring a number of resistance determinants, including MBLs. Dually guanidinylated and C-5-alkylated analogs of nebramine were able to sensitize MBL-carrying P. aeruginosa to various BL–BLIs. The amphiphilic nebramine derivative, compound 4, synergized with multiple β-lactam antibiotics and BL–BLIs including aztreonam–avibactam (ATM–AVI), FEP–TAN and MEM–XER against multidrug-resistant P. aeruginosa isolates. In particular, compound 4 + ATM–AVI, restored susceptibility to all nine β-lactamase (including MBL)-harbouring P. aeruginosa strains that were previously resistant to aztreonam. Compound 4 was found to be less toxic than both polymyxin B and its corresponding amphiphilic tobramycin counterpart (compound 7) in human renal cell lines, RPTEC and HK-2. Overall, our study suggests that addition of compound 4 alongside next-generation BL–BLIs such as FEP–TAN, MEM–XER as well as the recently approved ATM–AVI combination can overcome intrinsic and acquired in vitro P. aeruginosa resistance determinants that confer high-level resistance to β-lactam antibiotics.

We describe the structure–activity relationship studies of galactose-based glycosylated antitumor ether lipids (GAELs) by installing amine groups at different positions of galactose and the glycerol backbone. Different dibasic and tribasic analogues of galacto-GAELs were synthesized and tested against a panel of human epithelial cancer cell lines. A β-anomeric triamino galactose scaffold, was the most active compound of the series and displayed CC₅₀ in the range of 2.6 ± 0.2 μM to 6.5 ± 0.1 μM against various epithelial cancer cell lines. This compound exhibited superior activity to kill cancer cells than cisplatin. The hit GAEL compound did not induce caspase activation and therefore, the cell-killing effect does not occur due to caspase-mediated apoptosis. This observation is in line with the previously reported GAEL prototypes.

Pseudomonas aeruginosa is an opportunistic critical ‘priority 1’ Gram-negative bacterium that poses a severe threat to public healthcare due to rising antibiotic resistance.

Multicomponent therapy combining antibiotics with enhancer molecules known as adjuvants is an emerging strategy to combat antimicrobial resistance. Niclosamide is a clinically relevant anthelmintic drug with potential to be repurposed for its inherent antibacterial activity against Gram‐positive bacteria and its ability to potentiate the antibacterial activity of colistin against susceptible and resistant Gram‐negative bacteria. Herein, sulfonamide analogs of niclosamide were prepared and found to enhance colistin activity against Gram‐negative bacteria. The ability of niclosamide and the new sulfonamide analogs to synergize with bacitracin against vancomycin‐resistant Enterococcus faecium was also discovered.

The emergence of aminoglycoside resistance has prompted the development of amphiphilic aminoglycoside derivatives which target bacterial membranes. Tobramycin and nebramine ether derivatives initially designed for this purpose were optimized and screened for their potential application as outer membrane (OM) permeabilizing adjuvants. Structure–activity relationship (SAR) studies revealed that the tobramycin benzyl ether was the most optimal OM permeabilizer, capable of potentiating rifampicin, novobiocin, vancomycin, minocycline, and doxycycline against Gram-negative bacteria. The innovative use of this compound as an adjuvant is highlighted by its ability to sensitize multidrug-resistant (MDR) Gram-negative bacteria to rifampicin and restore the susceptibility of MDR Escherichia coli to minocycline.

Colistin is primarily used as a last resort antibiotic against highly resistant Gram-negative bacteria (GNB). Rising rates of colistin resistance, however, may limit future use of this agent. The anthelmintic drug niclosamide has been shown to enhance colistin activity in combination therapy, but a detailed structure–activity relationship (SAR) for niclosamide against GNB has yet to be studied. A series of niclosamide analogs were synthesized to perform an SAR, leading to the discovery of a lead compound that displayed comparable colistin-potentiating activity to niclosamide with reduced cytotoxicity. Overall, this work provides important insights into synthetic strategies for the future development of new niclosamide derivatives and demonstrates that toxicity to mammalian cells can be reduced while maintaining colistin potentiation.

Carbapenem-resistant Pseudomonas aeruginosa (P. aeruginosa) was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid dissemination of β-lactamases in P. aeruginosa, β-lactam (BL) antibiotics are used in conjunction with β-lactamase inhibitors (BLI). The effectiveness of the BL/BLI combination could be further enhanced with the inclusion of an outer membrane (OM) permeabilizer, such as aminoglycosides and aminoglycoside-based adjuvants. Thus, the development of seven tobramycin derivatives reported herein focused on improving OM permeabilizing capabilities and reducing associated toxicity. The structure-activity relationship studies emphasized the effects of the nature of the cationic group; the number of polar head groups and positive charges; and flexibility, length, and steric bulk of the hydrophobic moiety. The optimized guanidinylated tobramycin-biphenyl derivative was noncytotoxic and demonstrated the ability to potentiate ceftazidime and aztreonam monotherapy and in dual combinations with avibactam against multidrug-resistant (MDR) and β-lactamase harboring isolates of P. aeruginosa. The triple combination of ceftazidime/avibactam plus guanidinylated tobramycin-biphenyl resulted in rapid bactericidal activity within 4-8 h of treatment, demonstrating the potential application of these guanidinylated amphiphilic tobramycin derivatives in augmenting BL/BLI combinations.