A ferritin-like diiron oxygenase BioE initiates bacterial biotin synthesis, a promising antivirulence target.

Abstract

Biotin is an essential enzyme cofactor for intermediary metabolism, and its importance is reflected by the multiplicity of bacterial pathways to its universal precursor, pimelic acid. Here, we report identification of a fourth pimeloyl pathway in the rare but clinically important pathogens <i>Elizabethkingia</i> and <i>Chryseobacterium</i>. This pathway is encoded by two associated structural genes, <i>bioE</i> and <i>bioL</i>. BioE is a ferritin-like nonheme diiron oxygenase that oxidatively cleaves saturated C_n (n = 14, 16, 18) fatty acyl coenzyme A (CoA) or acyl carrier protein (ACP) substrates to pimeloyl-CoA/ACP and the free C_n-7 acid. The catalytic activity was demonstrated by both in vitro enzymatic assays and the capacity of the <i>bioE</i> gene to complement the genetic defect of an <i><i>Escherichia coli</i></i> biotin indicator strain that cannot produce the pimeloyl precursor. BioL, an unusual MocR-type bifunctional transcription factor, negatively regulates <i>bioE</i> expression in response to binding of the downstream intermediate 7-keto-8-aminopelargonic acid. Disruption of <i>bioE</i> in <i>Elizabethkingia meningoseptica</i> and <i>Chryseobacterium indologenes</i> makes them auxotrophic for biotin, impairs biofilm formation, and attenuates bacterial infectivity. Taken together, our findings expand enzymatic diversity of biotin biosynthesis and suggest that selective inhibition of this BioE pathway could provide a therapeutic strategy against recalcitrant nosocomial infections caused by these multidrug-resistant pathogens.