The N-terminal Region of Nisin Is Important for the BceAB-Type ABC Transporter NsrFP from Streptococcus agalactiae COH1

Reiners, Jens; Lagedroste, Marcel; Ehlen, Katja; Leusch, Selina; Zaschke-Kriesche, Julia; Smits, Sander H. J.

doi:10.3389/fmicb.2017.01643

Cited by 30 publications

(65 citation statements)

References 47 publications

(81 reference statements)

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“…This was not in line with our hypothesis that BceAB should expel bacitracin from the membrane into the extracellular milieu. In a recent study on the BceAB-type transporter NsrFP from Streptococcus agalactiae COH1, which used a similar peptide release assay, the residual AMP concentration in the culture supernatant was significantly higher in an nsrFP ϩ strain than strains with no or inactive NsrFP, in agreement with a hydrophobic vacuum cleaner mechanism as proposed for BceAB (20). It is therefore tempting to speculate that BceAB works by a similar mechanism, considering that both proteins are closely related and members of the same type of transporters, even though our bioassay data are not conclusive on the direction of transport.…”

Section: Resultssupporting

confidence: 64%

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BceAB-Type Antibiotic Resistance Transporters Appear To Act by Target Protection of Cell Wall Synthesis

Kobras

Piepenbreier

Emenegger

et al. 2020

Antimicrob Agents Chemother

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Resistance against cell wall-active antimicrobial peptides in bacteria is often mediated by transporters. In low-GC-content Gram-positive bacteria, a common type of such transporters is BceAB-like systems, which frequently provide highlevel resistance against peptide antibiotics that target intermediates of the lipid II cycle of cell wall synthesis. How a transporter can offer protection from drugs that are active on the cell surface, however, has presented researchers with a conundrum. Multiple theories have been discussed, ranging from removal of the peptides from the membrane and internalization of the drug for degradation to removal of the cellular target rather than the drug itself. To resolve this much-debated question, we here investigated the mode of action of the transporter BceAB of Bacillus subtilis. We show that it does not inactivate or import its substrate antibiotic bacitracin. Moreover, we present evidence that the critical factor driving transport activity is not the drug itself but instead the concentration of drug-target complexes in the cell. Our results, together with previously reported findings, lead us to propose that BceAB-type transporters act by transiently freeing lipid II cycle intermediates from the inhibitory grip of antimicrobial peptides and thus provide resistance through target protection of cell wall synthesis. Target protection has so far only been reported for resistance against antibiotics with intracellular targets, such as the ribosome. However, this mechanism offers a plausible explanation for the use of transporters as resistance determinants against cell wall-active antibiotics in Gram-positive bacteria where cell wall synthesis lacks the additional protection of an outer membrane.

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Section: Resultssupporting

confidence: 64%

“…Nevertheless, based on the homology between BceAB and NsrFP, it is plausible that both employ the same functional mechanism (20). Further support for the expulsion of AMPs from the membrane may be provided by the LanFEG-type transporters, which use such a strategy to confer self-immunity in AMP-producing bacteria.…”

Section: Resultsmentioning

confidence: 99%

BceAB-Type Antibiotic Resistance Transporters Appear To Act by Target Protection of Cell Wall Synthesis

Kobras

Piepenbreier

Emenegger

et al. 2020

Antimicrob Agents Chemother

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“…lipid II or UPP) and the AMP based on previous studies and transporter activity studies in presence of more UPP or in presence of C35 isoprenoid heptaprenyl diphosphate (HPP) (28). Those results disprove previous assumptions of an UPP flippase mechanism (27) and indicate a potential target-AMP-dissociation mechanism until the results of this study are taken into consideration.…”

Section: Discussionsupporting

confidence: 86%

“…A study on the BceAB transporter of B. subtilis postulates flipping of UPP in order to remove the bacitracin target and thus to confer resistance against bacitracin (27). However, UPP flipping would not explain the additional resistance against nisin and gallidermin (37).…”

Section: Discussionmentioning

confidence: 99%

“…The BceAB-type transporter, which was first discovered in B. subtilis (23) is encoded on one operon together with the BceRS-like two component system (TCS) which regulates the expression of the transporter (24). Several putative mechanisms have been proposed for BceAB-type transporter ranging from antimicrobial peptide removal from the membrane (25), operating as an exporter (26) or flipping UPP, a sub-product of the peptidoglycan synthesis (27). More recently a study proposed a target-AMP dissociative mechanism for BceAB-type transporters (28).…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of BceAB-type transporter: Resistance by lipid II flipping

Zaschke-Kriesche

Unsleber

Voitsekhovskaia

et al. 2020

Preprint

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Treatment of bacterial infections are the great challenge of our era due to the evolved resistance mechanisms against antibiotics. The Achilles heel of bacteria is the cell wall especially during the needs of its synthesis and cell division. Here lipid II is an essential cell wall precursor component synthesized in the cytosol and flipped into the outer leaflet of the membrane prior to its incorporation into the cell wall. Compounds targeting the cell wall or its biosynthesis precursors have been around for decades and have been used as antibiotics against bacterial infections like meningitis, pneumonia and endocarditis. Antimicrobial peptides (AMPs) have proven to be a promising weapon against multiresistant bacteria. However, the Bacitracin efflux (BceAB)-type ATP binding cassette transporters expressed in the membrane of human pathogenic bacteria have been shown to confer resistance to these alternative antibiotics, thereby hampering their medical development.In Streptococcus agalactiae COH1 the BceAB-type transporter NsrFP (SaNsrFP) confers highlevel resistance against the antimicrobial peptide nisin, a member of the lantibiotic subfamily. We showed that SaNsrFP provides a novel resistance mechanism by flipping lipid II back into the cytosol, thereby preventing the binding of nisin as well as other lipid II targeting compounds. This is intriguing since a relatively simple reaction mediates resistance to human pathogenic bacteria to lipid II targeting antibiotics, regardless of their structure. Significance StatementThe ABC-transporter NsrFP from Streptococcus agalactiae (SaNsrFP) belongs to the BceAB-type transporters. Several BceAB-type transporters are known to confer resistance against multiple antimicrobial peptides. In this study a new resistance mechanism was identified, which is based on the reduction of the number of cell wall precursor lipid II molecules on the cell surface mediated by SaNsrFP. SaNsrFP flips lipid II, which are considered to be the target for many antibiotics, back into the cytoplasm. With this newly gained knowledge about the resistance mechanism of BceAB-type transporters, novel strategies can be established to overcome or bypass this resistance in human pathogenic bacteria. Main Text

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Self‐immunity to antibacterial peptides by ABC transporters

2020

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Bacteria produce under certain stress conditions bacteriocins and microcins that display antibacterial activity against closely related species for survival. Bacteriocins and microcins exert their antibacterial activity by either disrupting the membrane or inhibiting essential intracellular processes of the bacterial target. To this end, they can lyse bacterial membranes and cause subsequent loss of their integrity or nutrients, or hijack membrane receptors for internalisation. Both bacteriocins and microcins are ribosomally synthesised and several are posttranslationally modified, whereas others are not. Such peptides are also toxic to the producer bacteria, which utilise immunity proteins or/and dedicated ATP-binding cassette (ABC) transporters to achieve self-immunity and peptide export. In this review, we discuss the structure and mechanism of self-protection that is conferred by these ABC transporters.

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The N-terminal Region of Nisin Is Important for the BceAB-Type ABC Transporter NsrFP from Streptococcus agalactiae COH1

Cited by 30 publications

References 47 publications

BceAB-Type Antibiotic Resistance Transporters Appear To Act by Target Protection of Cell Wall Synthesis

BceAB-Type Antibiotic Resistance Transporters Appear To Act by Target Protection of Cell Wall Synthesis

Mechanism of BceAB-type transporter: Resistance by lipid II flipping

Self‐immunity to antibacterial peptides by ABC transporters

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