Cell-density dependent chemical communication known as quorum sensing regulates virulence in bacterial pathogens, such as Pseudomonas aeruginosa. In gram-negative bacteria, quorum sensing is regulated by small organic molecules known as N-acyl homoserine lactons (AHLs). It was recently proposed that an intramolecular n→π* orbital overlap is present in AHLs that affords enhanced stability of the butyrolactone moiety under physiological conditions. We sought to experimentally determine the presence or absence of the n→π* orbital overlap and the magnitude of its contribution to AHL hydrolytic stability. To do so, a novel series of AHL analogs containing electron-withdrawing and donating groups were synthesized and their relative hydrolysis rates were monitored. The experimental data was then coorelated to (NBO) energies from the lowest energy confromations of each analog using density functional theory (DFT) calculations at the B3LYP/6311+G(2d,p) level of theory. A distinct hydrolysis rate was observed for each analog, ranging from 1.73 x 10-4 to 4.56 x 10-4 mM/min, proving that the EDGs and EWGs manipulated the stability of the lactone ring. In addition, computational models of the AHL derivatives show a correlation between the experimentally obtained hydrolysis rates, key dihedral angles in the AHL, and the strength of the n→π* interaction. Thus, exploiting the n→π* overlap in small molecule design may help in the development of more potent quorum sensing agonists and antagonists.

Experimental evidence of a stabilizing n→π* interaction in N-acyl homoserine lactone (AHL) hydrolysis

254th National Meeting (2017)

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