Teresa Rocha
PC30 – Teresa Rocha
Faculty of Medicine of University of Porto, Portugal
up202005935@edu.fc.up.pt
| Balancing the potency and toxicity of novel antimicrobial agents by rational design |
| Rocha Teresa1, Nunes Bárbara2,3, Simões Manuel2,3, Fernandes Carlos1, Borges Fernanda1, Cagide Fernando1 1 RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto 2 LEPABE – Laboratory for Process Engineering, Biotechnology and Energy, Faculty of Engineering, University of Porto 3 ALiCE–Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto |
| Abstract Antimicrobial resistance (AMR) is one of the greatest threats facing human health worldwide, as drug-resistant pathogens increasingly compromise available treatment options. Despite the recognised urgency, only a few novel antibiotic classes have reached the clinic in recent decades, highlighting the critical need for novel antimicrobial agents. Quaternary ammonium (QAS) and quaternary phosphonium (QPS) salts have emerged as promising candidates due to their broad-spectrum activity and tunable molecular scaffold. Previous studies demonstrated the potent antimicrobial efficacy of dodecyl and tetradecyl triphenylphosphonium (TPP) derivatives against S. aureus, A. baumannii, E. coli, and C. albicans. However, significant cytotoxic and hemolytic effects were reported, limiting their therapeutic potential [1,2]. To address this, two rational design strategies were pursued: (i) conjugation of the TPP phenyl rings with fatty acid chains, and (ii) change of the phosphonium headgroup with QAS bearing electron-withdrawing groups. A small library of fluorinated pyridinium, isoquinolinium, quinolinium, and methylpiperidinium salts with dodecyl and tetradecyl chains, and TPP-fatty acid conjugates, was synthesised. Antimicrobial activity was assessed against an antibiotic-susceptible S. aureus strain and extended to a clinically relevant panel of Gram-positive, Gram-negative bacteria, and fungi (C. albicans, C. neoformans). Cytotoxicity was evaluated in HepG2 and NHDF cell lines, and mitochondrial membrane polarisation and mitochondrial mass were assessed. All compounds inhibited S. aureus growth within the same low micromolar range as TPP analogues. Six showed relevant broad-spectrum antibacterial and/or antifungal activities. Based on activity and chemical diversity, a subset of compounds was selected for cytotoxicity evaluation, revealing a significantly improved profile relative to TPP analogues. Mitochondrial data confirmed that toxicity was dependent on mitochondrial function. This work provides a rational framework to optimise fluorinated QAS-based antimicrobial agents enhancing their potency while reducing cell host toxicity. |
| References [1] Nunes, B.; et al. Efficacy of Novel Quaternary Ammonium and Phosphonium Salts Differing in Cation Type and Alkyl Chain Length against Antibiotic-Resistant Staphylococcus aureus. Int. J. Mol. Sci., 2024, 25, 504, DOI: 10.3390/ijms25010504. [2] Nunes, B.; et al. Antimicrobial activity and Cytotoxicity of Novel Quaternary Ammonium and Phosphonium Salts. J. Mol. Liq., 2024, 401, 124616, DOI: 10.1016/j.molliq.2024.124616.z Acknowledgments: This work was funded by FEDER funds through the Operational Program Competitiveness Factors COMPETE and national funds by the FCT-Foundation for Science and Technology under research grants for RISE-Health (UID/06397/2025,) a C.L. (UI/BD/154557/2023) and B.A (2025.00893.BD) grant and D.C. (2024.07926.CEECIND) and S.B. (2023.06106.CEECIND/CP2833/CT0003) contracts were also supported by FCT and FEDER/COMPETE funds. |