Researchers made new chemical compounds that block a bacterial enzyme called SufA, which helps certain harmful bacteria cause infection. Two of these compounds, named 8a and 8c, showed good antibacterial activity and even helped protect the natural immune peptide LL‑37, but the work is still at the lab‑test stage and not ready for personal use.

This study aims to develop novel antibacterial agents by targeting SufA protease, a key virulence factor in Finegoldia magna, using 1-aminoalkylphosphonate (1-AAP) diaryl esters as inhibitors. Structural optimization of a reference inhibitor, Cbz-6-AmNpthP(OC&#x2086;H&#x2085;)&#x2082;, was performed by introducing substituents at the para position of phenyl rings: -SCH&#x2083; (<b>8a</b>), -OCH&#x2083; (<b>8b</b>), and -COOCH&#x2083; (<b>8c</b>). Enzymatic assays, molecular modeling, antibacterial activity screening, and CD spectroscopy were utilized to evaluate inhibitory potency, binding interactions, functional effects, and DNA interaction. Compound <b>8a</b> demonstrated moderate SufA inhibition (k&#x2082;/K_i&#x2009;=&#x2009;1500&#x2009;M^{- 1} s^{- 1}), supported by molecular modeling that showed stable binding via hydrogen bonding and &#x3c0;-&#x3c0; stacking. It also protected host defense molecules (fibrinogen, LL-37) and exhibited broad-spectrum antibacterial activity (IC&#x2085;&#x2080;&#x2009;=&#x2009;0.02&#x2009;&#xb5;M against S. marcescens and F. magna). Compound 8c, despite weak SufA inhibition, displayed potent antibacterial activity (IC&#x2085;&#x2080;&#x2009;&lt;&#x2009;0.01&#x2009;&#xb5;M), surpassing gentamicin. 1-AAP derivatives, particularly 8a and 8c, exhibit promising antibacterial properties. These findings validate SufA as a therapeutic target and support further development of peptide-based inhibitors to enhance efficacy and selectivity.