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; Robinson, John A.; Obrecht, Daniel

doi:10.1038/s41586-019-1665-6

Cited by 260 publications

(277 citation statements)

References 28 publications

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“…This is reminiscent of a previous report that showed that exogenous spermine and spermidine increased the MIC of imipenem against P. aeruginosa Lu, 2006, 2007), likely by blocking the OM porin OprD, which facilitates the penetration of imipenem through the OM (Hancock and Brinkman, 2002). Collectively, these data suggest that the peptidomimetics have specific and complex interactions with the negatively charged cell envelope, perhaps through interactions with OM proteins such as BamA, a known target of these antibiotics (Luther et al, 2019).…”

Section: Spermidine Protects Cells Against L27-11supporting

confidence: 75%

“…and BamA (Luther et al, 2019). In contrast, L27-11, which targets the OM protein LptD, showed fewer overlaps with the other antibiotics (9 with the POLs and 14 with peptides 3 and 4).…”

Section: Figure 3 | Number and Clustering Of Fitness Determinants (A)mentioning

confidence: 95%

“…A more recently described family of chimeric peptides (referred to as chimeras), including compounds 3 and 4, show potent bactericidal activity against all the Gram-negative ESKAPE pathogens E. coli, P. aeruginosa, A. baumanii, and K. pneumoniae. These compounds bind to both LPS and the main component (BamA) of the β-barrel folding complex (BAM; Figures 1A,B) required for the folding and insertion of β-barrel proteins into the OM of Gram-negative bacteria (Luther et al, 2019). At present, these antimicrobial peptides are in preclinical development, however, knowledge about the mechanisms of resistance against these new classes of peptidomimetic antibiotics is scarce.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing

et al. 2020

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Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of nosocomial infections. Due to its high intrinsic and adaptive resistance to antibiotics, infections caused by this organism are difficult to treat and new therapeutic options are urgently needed. Novel peptidomimetic antibiotics that target outer membrane (OM) proteins have shown great promise for the treatment of P. aeruginosa infections. Here, we have performed genome-wide mutant fitness profiling using transposon sequencing (Tn-Seq) to identify resistance determinants against the recently described peptidomimetics L27-11, compounds 3 and 4, as well as polymyxin B2 (PMB) and colistin (COL). We identified a set of 13 core genes that affected resistance to all tested antibiotics, many of which encode enzymes involved in the modification of the lipopolysaccharide (LPS) or control their expression. We also identified fitness determinants that are specific for antibiotics with similar structures that may indicate differences in their modes of action. These results provide new insights into resistance mechanisms against these peptide antibiotics, which will be important for future clinical development and efforts to further improve their potency.

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Section: Spermidine Protects Cells Against L27-11supporting

confidence: 75%

“…and BamA (Luther et al, 2019). In contrast, L27-11, which targets the OM protein LptD, showed fewer overlaps with the other antibiotics (9 with the POLs and 14 with peptides 3 and 4).…”

Section: Figure 3 | Number and Clustering Of Fitness Determinants (A)mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing

et al. 2020

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“…6,7 The last new class of antibiotics that target the Gram-negative bacteria are the synthetic uoroquinolones which were introduced into the clinic about 50 years ago. 8,9 The high rate of the rediscovery of old known molecules in traditional natural product (NP) screening platforms makes this grim situation even worse. Thus, the research community must nd new sources of NPs to cope with the looming antibiotic crisis.…”

Section: Introductionmentioning

confidence: 99%

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

Maglangit

Deng

2021

Nat. Prod. Rep.

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“…The ESKAPE pathogens are commonly associated with antimicrobial resistance . Of particular concern are the Gram‐negative bacteria (GNB) ESAKPE pathogens Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp .…”

Section: Introductionmentioning

confidence: 99%

A Glycosylated Cationic Block Poly(β‐peptide) Reverses Intrinsic Antibiotic Resistance in All ESKAPE Gram‐Negative Bacteria

Lim

Tay

et al. 2020

Angewandte Chemie

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Carbapenem-resistant Gram-negative bacteria (GNB) are heading the list of pathogens for whicha ntibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer-membrane or are excluded by efflux mechanisms.Here,wereport acationic block b-peptide (PAS8-b-PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8-b-PDM12 does not only compromise the integrity of the bacterial outermembrane,italso deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As ar esult, PAS8-b-PDM12 sensitizes carbapenem-and colistin-resistant GNB to multiple antibiotics in vitro and in vivo.The b-peptide allows the perfect alternation of cationic versus hydrophobic side chains,r epresenting as ignificant improvement over previous antimicrobial a-peptides sensitizing agents.T ogether, our results indicate that it is technically possible for as ingle adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group,i ncluding those resistant to last resort antibiotics. Singapore 637551 (Singapore) Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Chimeric peptidomimetic antibiotics against Gram-negative bacteria

Cited by 260 publications

References 28 publications

Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing

Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

A Glycosylated Cationic Block Poly(β‐peptide) Reverses Intrinsic Antibiotic Resistance in All ESKAPE Gram‐Negative Bacteria

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