Author Correction: Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Luther, Anatol; Urfer, Matthias; Zahn, Michael; Müller, Marion; Wang, Shuangyan; Mondal, Milon; Vitale, Alessandra; Hartmann, Jean-Baptiste; Sharpe, Timothy; Monte, Fabio Lo; Kocherla, Harsha; Cline, Elizabeth; Pessi, Gabriella; Rath, Parthasarathi; Modaresi, Seyed Majed; Chiquet, Petra; Stiegeler, Sarah; Carolin, Verbree; Remus, Tobias; Schmitt, Michel; Kolopp, Caroline; Westwood, Marie-Anne; Desjonquères, Nicolas; Brabet, Emile; Hell, Sophie; LePoupon, Karen; Vermeulen, Annie; Jaisson, Régis; Rithié, Virginie; Upert, Grégory; Lederer, Alexander; Zbinden, Peter; Wach, Achim; Moehle, Kerstin; Zerbe, Katja; Locher, Hans H.; Bernardini, Francesca; Dale, Glenn E.; Eberl, Leo; Wollscheid, Bernd; Hiller, Sebastian; Obrecht, Daniel

doi:10.1038/s41586-019-1810-2

Cited by 7 publications

(6 citation statements)

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“…Spero therapeutics also recently completed first-in-human phase 1 clinical trials of the novel polymyxin analog SPR206, which showed no renal toxicity throughout a dosing regimen likely exceeding requirements for clinical efficacy [ 123 ]. Lastly, a series of polymyxin-derived chimeric peptidomimetics, containing the defining β-hairpin peptide macrocycle of polymyxins, were shown to target outer membrane biogenesis through binding both LPS and the BamA, an essential component of the β -barrel folding complex tasked with folding and inserting β -barrel proteins into the outer membrane [ 124 ]. The optimized derivatives demonstrated potent activity across multidrug-resistant gram-negative bacteria, and the lead candidate advanced into preclinical toxicology studies with hopes for first-in-human trials soon.…”

Section: Targeting Lps Transportmentioning

confidence: 99%

Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance

Romano

Hung

2023

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Section: Targeting Lps Transportmentioning

confidence: 99%

Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance

Romano

Hung

2023

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…The inner leaflet consists of glycerophospholipids, while the outer leaflet comprises lipopolysaccharides. This bilayer acts as a formidable barrier that hinders the diffusion of most drug molecules across the membrane (1,2). The OM encompasses various proteins known as outer membrane proteins (OMPs) that are essential for bacterial growth and pathogenesis, which include lipopolysaccharide (LPS) and capsular polysaccharide transporters, porins facilitating macromolecular uptake, and transporters responsible for vital elements such as iron (3).…”

Section: Introductionmentioning

confidence: 99%

“…OMPs play a critical role in maintaining structural and functional integrity within the OM of gram-negative bacteria(4). The antibiotic murepavadin, which specifically targets lipopolysaccharide transport protein D (LptD), or chimeric peptidomimetics that target BamA (involved in OMP transport and assembly) exhibit remarkable efficacy against MDR gramnegative bacterial strains in vivo and in vitro (1). Therefore, significant research interest is focused on developing novel antibacterial drugs that target specific functions associated with OMP molecules.…”

Section: Introductionmentioning

confidence: 99%

A peptide targeting outer membrane protein A ofAcinetobacter baumanniiexhibits antibacterial activity by reducing bacterial pathogenicity

Zhao,

Hu,

Nie

et al. 2024

Preprint

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The World Health Organization has classified multidrug-resistant (MDR) Acinetobacter baumannii as a significant threat to human health, necessitating the urgent discovery of new antibacterial drugs to combat bacterial resistance. Outer membrane protein A of A. baumannii (AbOmpA) is an outer membrane-anchored β?barrel-shaped pore protein that plays a critical role in bacterial adhesion, invasion, and biofilm formation. Therefore, AbOmpA is considered a key virulence factor of A. baumannii. Herein, we screened three phage display peptide libraries targeting AbOmpA and identified several peptides. Among them, P92 (amino acid sequence: QMGFMTSPKHSV) exhibited the highest binding affinity with AbOmpA, with a KD value of 7.84 nM. In vitro studies demonstrated that while P92 did not directly inhibit bacterial growth, it significantly reduced the invasion and adhesion capabilities of multiple clinical isolates of MDR A. baumannii and concentration-dependently inhibited biofilm formation by acting on OmpA. Furthermore, the polymerase chain reaction results confirmed a significant positive correlation between the antibacterial effect of P92 and OmpA expression levels. Encouragingly, P92 also displayed remarkable therapeutic efficacy against A. baumannii infection in various models, including an in vitro cell infection model, a mouse skin infection model, and a mouse sepsis model. These results highlight P92 as a novel and highly effective antimicrobial molecule specifically targeting the virulence factor AbOmpA.

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“…The molecular machine driving OMP insertion and assembly into the membrane is the β-barrel assembly machinery complex (BAM complex) ( Bakelar et al, 2016 ; Gu et al, 2016 ; Iadanza et al, 2016 ). Given this essential role, and its location on the bacterial cell surface, the BAM complex has emerged as an attractive antibiotic target ( Hart et al, 2019 ; Imai et al, 2019 ; Kaur et al, 2021 ; Luther et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Dual recognition of multiple signals in bacterial outer membrane proteins enhances assembly and maintains membrane integrity

Germany,

Thewasano,

Imai

et al. 2024

eLife

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Outer membrane proteins (OMPs) are essential components of the outer membrane of Gram-negative bacteria. In terms of protein targeting and assembly, the current dogma holds that a “β-signal” imprinted in the final β-strand of the OMP engages the β-barrel assembly machinery (BAM complex) to initiate membrane insertion and assembly of the OMP into the outer membrane. Here, we reveal an additional rule, that signals equivalent to the β-signal are repeated in other, internal β-strands within bacterial OMPs. The internal signal is needed to promote the efficiency of the assembly reaction of these OMPs. BamD, an essential subunit of the BAM complex, recognizes the internal signal and the β-signal, arranging several β-strands for rapid OMP assembly. The internal signal-BamD ordering system is not essential for bacterial viability but is necessary to retain the integrity of the outer membrane against antibiotics and other environmental insults. Bacterial outer membrane proteins are recognized and bound by BamD at specific signals located in multiple β-strands at the C-terminus of these proteins.

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Author Correction: Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Cited by 7 publications

References 0 publications

Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance

Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance

A peptide targeting outer membrane protein A ofAcinetobacter baumanniiexhibits antibacterial activity by reducing bacterial pathogenicity

Dual recognition of multiple signals in bacterial outer membrane proteins enhances assembly and maintains membrane integrity

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