Selective cleavage of a peptide antibiotic, colistin by colistinase.

Ito-Kagawa, Mikiko; Koyama, Yasuo

doi:10.7164/antibiotics.33.1551

Cited by 36 publications

(18 citation statements)

References 11 publications

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“…In contrast to PMBN, at high concentrations (30 µg/mL) PMBD displayed direct antimicrobial activity. The report by Kimura et al is in remarkable contrast to the report by Ito-Kagama and Koyama127,130 that showed an approximate 100-fold difference in OM permeabilizing activity of colistin nonapeptide and colistin heptapeptide. This discrepancy may be a result of the different preparative and purification procedures employed by the two groups.…”

Section: Sar Of Polymyxinsmentioning

confidence: 72%

Structure−Activity Relationships of Polymyxin Antibiotics

Velkov

Thompson²,

Nation³

et al. 2009

J. Med. Chem.

633

776

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Section: Sar Of Polymyxinsmentioning

confidence: 72%

Structure−Activity Relationships of Polymyxin Antibiotics

Velkov

Thompson²,

Nation³

et al. 2009

J. Med. Chem.

633

776

View full text Add to dashboard Cite

“…Polymyxins can be inactivated by Bacillus species. Studies from several decades ago indicated that colistin-inactivating enzymes are probably produced and secreted by the producer of colistin, P. polymyxa (20)(21)(22). To identify the colistin-inactivating enzyme, the cylinder-plate diffusion method was performed to screen colistin-degrading bacteria from our laboratory stocks of Bacillus strains.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of Polymyxin by Hydrolytic Mechanism

Yin

Wang

Cheng

et al. 2019

Antimicrob Agents Chemother

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Polymyxins are nonribosomal peptide antibiotics used as the last-resort drug for treatment of multidrug-resistant Gram-negative bacteria. However, strains that are resistant to polymyxins have emerged in many countries. Although several mechanisms for polymyxin resistance have been well described, there is little knowledge on the hydrolytic mechanism of polymyxin. Here, we identified a polymyxininactivating enzyme from Bacillus licheniformis strain DC-1 which was produced and secreted into the medium during entry into stationary phase. After purification, sequencing, and heterologous expression, we found that the alkaline protease Apr is responsible for inactivation of polymyxins. Analysis of inactivation products demonstrated that Apr cleaves polymyxin E at two peptide bonds: one is between the tripeptide side chain and the cyclic heptapeptide ring, the other between L-Thr and L-␣-␥-diaminobutyric acid (L-Dab) within the cyclic heptapeptide ring. Apr is highly conserved among several genera of Gram-positive bacteria, including Bacillus and Paenibacillus. It is noteworthy that two peptidases S8 from Gram-negative bacteria shared high levels of sequence identity with Apr. Our results indicate that polymyxin resistance may result from inactivation of antibiotics by hydrolysis. KEYWORDS Bacillus licheniformis, alkaline protease, polymyxin resistance, polymyxininactivating enzyme, polymyxins L-␣-␥-diaminobutyric acid (L-Dab) residues (Fig. 1). Due to the higher affinity between L-Dab and lipid A, polymyxins displace divalent cations and bind to lipid A molecules, resulting in destabilization of the outer membrane. The hydrophobic domains of polymyxins (including the fatty acyl chain and D-Phe/D-Leu-L-Leu) insert between the acyl chains of lipid A and then enter the periplasm via a self-promoted uptake mechanism. Subsequently, polymyxins penetrate into the phospholipid bilayer of the RESULTSPolymyxins can be inactivated by Bacillus species. Studies from several decades ago indicated that colistin-inactivating enzymes are probably produced and secreted by the producer of colistin, P. polymyxa (20)(21)(22). To identify the colistin-inactivating enzyme, the cylinder-plate diffusion method was performed to screen colistin-degrading bacteria from our laboratory stocks of Bacillus strains. Escherichiacoli strain DH5␣ was used as a colistin-sensitive indicator strain. The addition of colistin (10,000 U/ml) resulted in an FIG 1 Chemical structure and degradation pathway of colistin. The amino acid positions are numbered in accordance with the discussion in the text. The amino acid at position 6 is D-Phe in polymyxin B. Both colistin and PMB are mixtures of structurally related compounds. Fatty acid, 6-methyloctanoic acid for colistin A and PMB 1 and 6-methylheptanoic acid for colistin B and PMB 2

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“…Although enzymatic resistance of bacteria to polymyxins has not been reported, it is interesting that Bacillus polymyxa subsp. colistinus produces colistinase that inactivates colistin [26]. …”

Section: Discussionmentioning

confidence: 99%