Author Correction: A new antibiotic selectively kills Gram-negative pathogens

Imai, Yu; Meyer, Kirsten J.; Iinishi, Akira; Favre-Godal, Quentin; Green, Robert C.; Manuse, Sylvie; Caboni, Mariaelena; Mori, Miho; Niles, Samantha; Ghiglieri, Meghan; Honrao, Chandrashekhar; Ma, Xiaoyu; Guo, Jason; Makriyannis, Alexandros; Linares-Otoya, Luis; Böhringer, Nils; Wuisan, Zerlina G.; Kaur, Hundeep; Wu, Runrun; Mateus, André; Typas, Athanasios; Savitski, Mikhail M.; Espinoza, Josh L.; O’Rourke, Aubrie; Nelson, Karen E.; Hiller, Sebastian; Noinaj, Nicholas; Schäberle, Till F.; D’Onofrio, Anthony; Lewis, Kim

doi:10.1038/s41586-020-2063-9

Cited by 8 publications

(7 citation statements)

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“…The bicyclic heptapeptide darobactin A is a ribosomally synthesized, post-translationally modified peptide (RiPP) with antibiotic activities against diverse sets of Gram-negative bacteria including many clinically important pathogens . Darobactin A exhibits its antibiotic activity by inhibiting BamA, a protein in the Bam complex responsible for the assembly of proteins in the outer membrane of Gram-negative bacteria. , Darobactin A has a rigid β-strand conformation through the ether and C–C crosslinks on the heptapeptide core structure (W 1 –N 2 –W 3 –S 4 –K 5 –S 6 –F 7 , see Figure for the structure), which mimics the recognition signal of native substrates and blocks the open lateral gate of BamA . However, the mechanism by which this unique and biologically important bicyclic structure is formed remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Radical SAM Oxygenase for the Ether Crosslinking in Darobactin Biosynthesis

et al. 2022

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Darobactin A is a ribosomally synthesized, post-translationally modified peptide (RiPP) with potent and broad-spectrum anti-Gram-negative antibiotic activity. The structure of darobactin A is characterized by an ether and C–C crosslinking. However, the specific mechanism of the crosslink formation, especially the ether crosslink, remains elusive. Here, using in vitro enzyme assays, we demonstrate that both crosslinks are formed by the DarE radical S-adenosylmethionine (SAM) enzyme in an O2-dependent manner. The relevance of the observed activity to darobactin A biosynthesis was demonstrated by proteolytic transformation of the DarE product into darobactin A. Furthermore, DarE assays in the presence of 18O2 or [18O]water demonstrated that the oxygen of the ether crosslink originates from O2 and not from water. These results demonstrate that DarE is a radical SAM enzyme that uses oxygen as a co-substrate in its physiologically relevant function. Since radical SAM enzymes are generally considered to function under anaerobic environments, the discovery of a radical SAM oxygenase represents a significant change in the paradigm and suggests that these radical SAM enzymes function in aerobic cells. Also, the study revealed that DarE catalyzes the formation of three distinct modifications on DarA; ether and C–C crosslinks and α,β-desaturation. Based on these observations, possible mechanisms of the DarE-catalyzed reactions are discussed.

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Section: Introductionmentioning

confidence: 99%

Characterization of a Radical SAM Oxygenase for the Ether Crosslinking in Darobactin Biosynthesis

et al. 2022

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“…Generally, an antibiotic must reach the site of action to kill bacteria. However, Gram-negative bacteria have sophisticated cell envelopes as highly restrictive permeability barriers, which limits the intracellular penetration of most compounds. ,, The envelopes consist of two concentric membrane layers, the OM and the IM, which delimit the aqueous cellular compartment called periplasm. − Therefore, NPN and PI are used to evaluate the permeability level of OM and IM, respectively. NPN is a fluorescent molecule that cannot penetrate the intact OM.…”

Section: Resultsmentioning

confidence: 99%

“…coli ATCC 25922 were cultured to the exponential phase. Then, the bacteria were inoculated in fresh MHB containing 0.25, 0.5, 1, 2, and 4× MIC of drugs. , TET was used as a positive control. After 24 h of incubation at 200 rpm and 37 °C, the cultures were used to detect MICs of nanoTTO and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

Tea Tree Oil Nanoemulsion Potentiates Antibiotics against Multidrug-Resistant Escherichia coli

et al. 2022

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Extensive efforts are underway to overcome the rising prevalence of antibiotic resistance. Combination therapy may be a potential method to treat multidrug-resistant (MDR) bacterial infections. In this study, tea tree essential oil (TTO) nanoemulsion (nanoTTO) was used in combination with antibiotics to kill microbes. Results showed that nanoTTO enhanced the activities of multiple antibiotics against MDR Escherichia coli (E. coli), and its antimicrobial activity was not changed against bacteria that were cultured in the presence of nanoTTO for 30 passages. Further studies to visualize and quantify intracellular antibiotics concentrations identified that nanoTTO increased the drug accumulation in MDR E. coli by disrupting outer and inner membranes and inhibiting the AcrAB–TolC efflux pump involved in membrane permeability. In addition, nanoTTO was effective in enhancing antibiotic efficacy in the Galleria mellonella infection model and mouse peritonitis model, suggesting a potential strategy against MDR bacterial infections.

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“…In a classical sense, the most well-known structural classes are the α-helix and β-sheets through the pioneering work of Lehrer, Ganz, Boman, Zasloff, Hancock, and others [ 8 , 9 , 10 , 25 , 26 , 27 ]. In contrast, AMPs synthesized through extraribosomal pathways (e.g., the cyclic lipopeptides, polymyxins) [ 28 , 29 ], were known for several decades prior to the discovery of ribosomally synthesized AMPs [ 13 , 30 , 31 , 32 ]. While AMPs like the polymyxins and daptomycin are widely used clinically, those made exclusively of some of the 20 (excluding selenocysteine) conventional amino acids (including engineered derivatives of these AMPs) are yet to be clinically available.…”

Section: Properties and Limitations Of Natural Cationic Antimicrobmentioning

confidence: 99%

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

et al. 2020

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The increasing rate of antibiotic resistance constitutes a global health crisis. Antimicrobial peptides (AMPs) have the property to selectively kill bacteria regardless of resistance to traditional antibiotics. However, several challenges (e.g., reduced activity in the presence of serum and lack of efficacy in vivo) to clinical development need to be overcome. In the last two decades, we have addressed many of those challenges by engineering cationic AMPs de novo for optimization under test conditions that typically inhibit the activities of natural AMPs, including systemic efficacy. We reviewed some of the most promising data of the last two decades in the context of the advancement of the field of helical AMPs toward clinical development.

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Author Correction: A new antibiotic selectively kills Gram-negative pathogens

Cited by 8 publications

References 0 publications

Characterization of a Radical SAM Oxygenase for the Ether Crosslinking in Darobactin Biosynthesis

Characterization of a Radical SAM Oxygenase for the Ether Crosslinking in Darobactin Biosynthesis

Tea Tree Oil Nanoemulsion Potentiates Antibiotics against Multidrug-Resistant Escherichia coli

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

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