Insight into Two ABC Transporter Families Involved in Lantibiotic Resistance

Clemens, Rebecca; Zaschke-Kriesche, Julia; Khosa, Sakshi; Smits, Sander H. J.

doi:10.3389/fmolb.2017.00091

Cited by 38 publications

(35 citation statements)

References 57 publications

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“…The growth of the three strains L. lactis NZ9000Cm, L. lactis NZ9000NsrFP and L. lactis NZ9000NsrF H202A P was monitored online over a time period of 500 minutes (Figure 3A). A sublethal concentration of 0.3 nM nisin was added to the cultures at an OD of 0.5 (31 37)) to induce the expression of the Sa nsrfp gene. L. lactis NZ9000NsrFP entered the stationary phase two hours later than L. lactis NZ9000NsrF H202A P and L. lactis NZ9000Cm strain (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

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

Zaschke-Kriesche

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Voitsekhovskaia

et al. 2020

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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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Section: Resultsmentioning

confidence: 99%

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

Zaschke-Kriesche

Unsleber

Voitsekhovskaia

et al. 2020

Preprint

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“…HrtBA and MacB belong to the type 3 family (ABC3), based on amino acid sequence analyses 44 . The ABC3 family includes the 8-TMH transporters, such as LolCDE 45 , BceAB 46 , and FtsXE 47 . It is noteworthy that their substrates, such as lipoproteins, are anchored at the surface of the outer membrane leaflet prior to translocation.…”

Section: Discussionmentioning

confidence: 99%

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2020

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Gram-positive pathogenic bacteria acquire heme derived from the host hemoglobin as an iron source for their proliferation in blood. Since excess free heme is cytotoxic, they employ an ABC-type heme exporter, HrtBA, to overcome the toxicity. We biochemically characterized HrtBA, and determined the crystal structures of the exporter, alone and complexed with a heme analog or nucleotides. HrtBA adopts an eight transmembrane-helix structure with no substrate-translocation cavity, and thus is distinct from the classical ABC transporters with an alternating access mechanism. Our structural models revealed the sequential motions whereby HrtBA captures heme in the outer leaflet of the membrane, sequesters it in the transmembrane-helix bundle, and extrudes the bound heme upon ATP binding. The structural and functional data illustrate the novel efflux mechanism by which HrtBA detoxifies the heme accumulated in the membrane, providing insights toward antimicrobial agent development.

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“…In the study that first described and named this mechanism, the authors determined that the cue sensed by the bacteria is the presence of the antibiotic bacitracin. Bacitracin acts on the bacterial cell wall, and thereby indirectly impairs physiological functions of the bacterial cell (Clemens et al, 2018). The presence of bacitracin is not sensed directly by a receptor, but indirectly, via the activity of the ABC transporter BceAB of B. subtilis, which is located in the bacterial membrane and mediates antibiotic resistance by driving the efflux of bacitracin (Bernard et al, 2007;Dintner et al, 2014;Fritz et al, 2015).…”

Section: Regulatory Influence Of Membrane Transport Proteins and Intrmentioning

confidence: 99%

Protein Activity Sensing in Bacteria in Regulating Metabolism and Motility

2020

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Bacteria have evolved complex sensing and signaling systems to react to their changing environments, most of which are present in all domains of life. Canonical bacterial sensing and signaling modules, such as membrane-bound ligand-binding receptors and kinases, are very well described. However, there are distinct sensing mechanisms in bacteria that are less studied. For instance, the sensing of internal or external cues can also be mediated by changes in protein conformation, which can either be implicated in enzymatic reactions, transport channel formation or other important cellular functions. These activities can then feed into pathways of characterized kinases, which translocate the information to the DNA or other response units. This type of bacterial sensory activity has previously been termed protein activity sensing. In this review, we highlight the recent findings about this non-canonical sensory mechanism, as well as its involvement in metabolic functions and bacterial motility. Additionally, we explore some of the specific proteins and protein-protein interactions that mediate protein activity sensing and their downstream effects. The complex sensory activities covered in this review are important for bacterial navigation and gene regulation in their dynamic environment, be it host-associated, in microbial communities or free-living.

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Insight into Two ABC Transporter Families Involved in Lantibiotic Resistance

Cited by 38 publications

References 57 publications

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

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

This preprint has been taken down.

Protein Activity Sensing in Bacteria in Regulating Metabolism and Motility

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