Bypassing lantibiotic resistance by an effective nisin derivative |
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Authors: | Julia Zaschke-Kriesche Lara V. Behrmann Jens Reiners Marcel Lagedroste Yvonne Gröner Rainer Kalscheuer Sander H.J. Smits |
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Affiliation: | 1. Institute of Biochemistry, Heinrich-Heine-University Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany;2. Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany;3. Center for Structural Studies, Heinrich-Heine-University Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany |
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Abstract: | The need for new antibiotic compounds is rising and antimicrobial peptides are excellent candidates to fulfill this object. The bacteriocin subgroup lantibiotics, for example, are active in the nanomolar range and target the membranes of mainly Gram-positive bacteria. They bind to lipid II, inhibit cell growth and in some cases form pores within the bacterial membrane, inducing rapid cell death. Pharmaceutical usage of lantibiotics is however hampered by the presence of gene clusters in human pathogenic strains which, when expressed, confer resistance. The human pathogen Streptococcus agalactiae COH1, expresses several lantibiotic resistance proteins resulting in resistance against for example nisin.This study presents a highly potent, pore forming nisin variant as an alternative lantibiotic which bypasses the SaNSR protein. It is shown that this nisin derivate nisinC28P keeps its nanomolar antibacterial activity against L. lactis NZ9000 cells but is not recognized by the nisin resistance protein SaNSR.NisinC28P is cleaved by SaNSR in vitro with a highly decreased efficiency, as shown by an cleavage assay. Furthermore, we show that nisinC28P is still able to form pores in the membranes of L. lactis and is three times more efficient against SaNSR-expressing L. lactis cells than wildtype nisin. |
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Keywords: | Corresponding author at: Institute of Biochemistry, Heinrich-Heine-University Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany. Lantibiotic Nisin resistance protein Activity |
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