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YkrB is the main peptide deformylase in Bacillus subtilis, a eubacterium containing two functional peptide deformylases

Institute for Anti-infectives Research, Pharma Research, Bayer AG, D-42096 Wuppertal, Germany¹

Author for correspondence: Christoph Freiberg. Tel: +49 202 368461. Fax: +49 202 364116. e-mail: Christoph.Freiberg.CF{at}bayer-ag.de

Peptide deformylation is an essential process in eubacteria. The peptide deformylase Def has been suggested to be an attractive target for antibacterial drug discovery. Some eubacteria including medically important pathogens possess two def-like genes. Until now, the functionality of both genes has been tested only in Staphylococcus aureus with the result that one gene copy was functional. Here, expression of two functional def-like gene products in Bacillus subtilis is demonstrated. Besides the def gene, which is chromosomally located close to the formyltransferase gene fmt and which was overexpressed and biochemically tested previously, B. subtilis possesses a second def-like gene, called ykrB. The encoded protein is 32% identical to the def gene product. It was shown that either def or ykrB had to be present for growth of B. subtilis in rich medium (each was individually dispensable). Studies with a def/ykrB double deletion strain with xylose-inducible ykrB copy demonstrated that, besides def, the gene ykrB is a second cellular target of deformylase inhibitors such as the antibiotic actinonin. The gene products exhibited similar enzymic properties, exemplified by similar inhibition efficacy of actinonin in biochemical assays. Antibiotic susceptibility tests with different deletion strains and Northern analyses indicated that YkrB is probably the predominant deformylase in B. subtilis. It was shown that duplication of the deformylase function does not lead to an increased actinonin-resistance frequency in comparison to B. subtilis mutants carrying only one deformylase gene.

Keywords: underexpression mutants, antibiotic resistance, formyltransferase, actinonin, antibacterial target

Abbreviations: fMAS, N-formylmethionine-alanine-serine; IC₅₀, inhibitor concentration which inhibits 50% of enzyme activity; K_i, dissociation constant; K_m, Michaelis constant; MAS, methionine-alanine-serine; MLS, macrolide/lincosamide/streptogramin

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