Insect‐Derived Proline‐Rich Antimicrobial Peptides Kill Bacteria by Inhibiting Bacterial Protein Translation at the 70 S Ribosome

Krizsan, Andor; Volke, Daniela; Weinert, Stefanie; Sträter, Norbert; Knappe, Daniel; Hoffmann, Ralf

doi:10.1002/anie.201407145

Cited by 200 publications

(283 citation statements)

References 25 publications

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“…Chex1-Arg20 possesses high sequence homology to all oncocins, with the 10-residue sequence PYLPRPRPPR in the middle being identical. Structural differences at the residues extending this sequence to the N terminus (Arg6 in Chex1-Arg20) or C terminus (Orn in Onc72, D-Arg in Onc112, and Pro in Chex1-Arg20) may explain the slight differences observed, although these might also be related to other parts of the killing mechanism, such as penetration through the outer membrane or inhibition of the 70S ribosome (11,42). Further support that the PYLPRPRPPR motif is important for the YjiLMdtM-transporter system comes from pyrrhocoricin, which contains two substitutions (Pro1Ser and Arg7Thr) in this sequence, drosocin (four substitutions), and both apidaecins (three substitutions).…”

Section: Discussionmentioning

confidence: 99%

Influence of the yjiL-mdtM Gene Cluster on the Antibacterial Activity of Proline-Rich Antimicrobial Peptides Overcoming Escherichia coli Resistance Induced by the Missing SbmA Transporter System

Krizsan

Knappe

Hoffmann

2015

Antimicrob Agents Chemother

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In view of increasing health threats from multiresistant pathogens, antimicrobial peptides (AMPs) and, specifically, proline-rich AMPs (PrAMPs) have been investigated in animal models. PrAMPs enter bacteria via the ABC transporter SbmA and inhibit intracellular targets. We used phage transduction (Tn10 insertion) to screen by random mutagenesis for alternative uptake mechanisms for analogs of apidaecin 1b, a honeybee-derived PrAMP. All 24 apidaecin-resistant mutants had the Tn10 insertion in the sbmA gene. These sbmA::Tn10 insertion mutants and the Escherichia coli BW25113 ⌬sbmA (JW0368) strain were still susceptible to the bactenecin PrAMP Bac7(1-35) and oncocin PrAMPs Onc18 and Onc112, as well as to Chex1-Arg20, despite significantly reduced internalizations. In a second round of random mutagenesis, the remaining susceptibility was linked to the yjiLmdtM gene cluster. E. coli BW25113 and its ⌬yjiL null mutant (JW5785) were equally susceptible to all PrAMPs tested, whereas the BW25113 ⌬mdtM mutant was less susceptible to oncocins. The JW0368 yjiL::Tn10 transposon mutant (BS2) was resistant to all short PrAMPs and susceptible only to full-length Bac7 and A3-APO. Interestingly, PrAMPs appear to enter bacteria via MdtM, a multidrug resistance transporter (drug/H ؉ antiporter) of the major facilitator superfamily (MFS) that can efflux antibiotics, biocides, and bile salts. In conclusion, PrAMPs enter bacteria via ABC and MFS transporters that efflux antibiotics and cytotoxic compounds from the cytoplasm to the periplasm. There are rising death tolls due to drug-resistant bacteria among persons with weakened or suppressed immune systems. The worldwide spread of multiresistant or even extensively resistant bacteria has therefore triggered intense research efforts to identify novel antibiotic classes, especially those with new modes of action (1). In recent years, thousands of gene-encoded antimicrobial peptides (AMPs) have been identified in different organisms and investigated in vitro and often in vivo, with several being now pursued in preclinical studies (2, 3). Proline-rich AMPs (PrAMPs), which are produced by insects with typical lengths of 18 to 25 residues or in mammals with 40 to 60 residues, represent a promising class of antibiotics (3-6). Besides native PrAMPs, either shortened versions [e.g., bactenecin Bac7(1-35)] or chemically optimized versions (e.g., apidaecin 1b analogs Api88 and Api137 or oncocins Onc18, Onc72, and Onc112) and those with artificial sequences (e.g., A3-APO and its single-chain version Chex1-Arg20) were shown to be highly efficient against Gramnegative and partially even against Gram-positive bacteria in several different murine infection models (5, 7-12).PrAMPs appear to pass readily across the outer membrane of Gram-negative bacteria before they are actively transported into the cytoplasm by SbmA (13,14). This 406-residue-long integral inner membrane protein has common features with the ATPbinding cassette (ABC) transporters but lacks the nucleotide binding domain and requires an e...

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Section: Discussionmentioning

confidence: 99%

Influence of the yjiL-mdtM Gene Cluster on the Antibacterial Activity of Proline-Rich Antimicrobial Peptides Overcoming Escherichia coli Resistance Induced by the Missing SbmA Transporter System

Krizsan

Knappe

Hoffmann

2015

Antimicrob Agents Chemother

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“…We conclude that the target activity allows T9W to bind to the cell membrane, which is followed by disruption of the cytoplasmic membrane, the lethal event leading to bacterial cell death. However, the exact mechanism of action of AMPs can be multiple, and recently the antimicrobial mechanism has been putatively associated with cell wall biogenesis (32), conductive ATP transport (33), and inhibition of DNA and protein synthesis (34,35). But, here, the fast killing efficiency as well as the fluorescence and the microscopic studies indeed clearly indicated that the major target of the antimicrobial action of T9W is the bacterial membrane.…”

Section: Figmentioning

confidence: 96%

Bactericidal Efficiency and Modes of Action of the Novel Antimicrobial Peptide T9W against Pseudomonas aeruginosa

Zhu

Shan

et al. 2015

Antimicrob Agents Chemother

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The antipseudomonal efficiency and mechanism of action of a novel engineered antimicrobial peptide, T9W, were evaluated in this study. T9W displayed high activity, with a lethal concentration (LC) of 1 to 4 M against Pseudomonas aeruginosa, including against ciprofloxacin-, gentamicin-, and ceftazidime-resistant strains, even in the presence of 50 to 300 mM NaCl, 1 to 5 mM Ca 2؉ , or 0.5 to 2 mM Mg 2؉ . The time-kill curve (TKC) analysis demonstrated concentration-dependent activity, with T9W achieving complete killing in less than 30 min at 1؋ LC and in less than 5 min at 4؋ LC. Combination TKC analyses additionally demonstrated a synergistic effect with ciprofloxacin and gentamicin. The selectivity of T9W was further supported by its ability to specifically eliminate P. aeruginosa in a coculture with macrophages without toxicity to the mammalian cells. The results from fluorescent measurement indicated that T9W bound to lipopolysaccharide (LPS) and induced P. aeruginosa membrane depolarization, and microscopic observations and flow cytometry further indicated that T9W targeted the P. aeruginosa cell membrane and disrupted cytoplasmic membrane integrity, thereby causing cellular content release leading to cell death. This study revealed the potential usefulness of T9W as a novel antimicrobial agent against P. aeruginosa.

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“…For instance, the bacterial peptide microcin J25 (MccJ25) inhibits RNA polymerase, 8 while apidaecins (in honeybees), oncocins (in insects), and Bactenecin-7 (in mammalian cells) inhibit bacterial translation by binding to ribosomal proteins. 9,10 …”

Section: Cationic Antimicrobial Peptides (Camps) and Bacterial Resistmentioning

confidence: 99%

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

Fields

Roy

2017

RNA Biology

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ABSTRACTtRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed.

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Insect‐Derived Proline‐Rich Antimicrobial Peptides Kill Bacteria by Inhibiting Bacterial Protein Translation at the 70 S Ribosome

Cited by 200 publications

References 25 publications

Influence of the yjiL-mdtM Gene Cluster on the Antibacterial Activity of Proline-Rich Antimicrobial Peptides Overcoming Escherichia coli Resistance Induced by the Missing SbmA Transporter System

Influence of the yjiL-mdtM Gene Cluster on the Antibacterial Activity of Proline-Rich Antimicrobial Peptides Overcoming Escherichia coli Resistance Induced by the Missing SbmA Transporter System

Bactericidal Efficiency and Modes of Action of the Novel Antimicrobial Peptide T9W against Pseudomonas aeruginosa

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

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