Title : Design, synthesis, and antimicrobial evaluation of a naphthalene-based conjugated oligoelectrolyte against resistant pathogens
Abstract:
Antimicrobial resistance (AMR) is a growing global health crisis, projected to cause up to 10 million deaths annually by 2050, imposing significant economic and healthcare burdens. Methicillin-resistant Staphylococcus aureus (MRSA) accounted for 121,000 AMR-related deaths in 2022. Despite this urgent threat, the discovery of new antibiotics has stagnated, highlighting the need for novel antimicrobial agents.
Conjugated oligoelectrolytes (COEs) are synthetic amphiphilic molecules comprising a conjugated π-core and terminal cationic groups (ammonium or phosphonium). These molecules are hypothesized to disrupt bacterial membranes, providing broad-spectrum activity against resistant pathogens. However, existing COEs face challenges such as suboptimal selectivity, toxicity, and complex synthesis.
Here, we present a novel class of naphthalene-based COEs featuring a streamlined two-step synthesis with a single purification step. This class includes COE-2SP (phosphonium) and COE-2SA (ammonium), both demonstrating potent activity against ESKAPE pathogens. COE-2SP exhibits broad-spectrum activity, including efficacy against Non-tuberculous Mycobacteria (NTM) (MIC₉₀ = 4 µg/mL), while COE-2SA is highly selective for MRSA with an exceptional selectivity index (MIC₉₀/IC₅₀ = 51). These pathogens are major contributors to respiratory and wound infections.
Time-kill assays reveal COE-2SA’s superior bactericidal action, achieving complete MRSA eradication within 1 hour, outperforming the standard antibiotic vancomycin. This study highlights the therapeutic potential of COEs as next-generation antimicrobial agents, offering a promising strategy to combat drug-resistant bacterial infections.
