Purification of lincosaminide O-nucleotidyltransferase from Streptomyces coelicolor Mueller.

Marshall, Vincent P.; McGee, J; Cialdella, J. I.; Baczynskyj, L.; Chirby, D. G.; Yurek, David A.; Liggett, W. F.; Kuo, M. S.

doi:10.7164/antibiotics.44.895

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…The biochemical mechanism of resistance differs from that reported for staphylococcal enzymes which catalyze the conversion of lincomycin to its 3-(5Ј-ribonucleotide) and clindamycin to its 4-(5Ј-ribonucleotide) (5). By contrast, the mechanism is similar to that reported for Streptomyces coelicolor Müller NRRL 3532 (25). It has been proposed that genes for antibiotic resistance originated in antibiotic producers.…”

Section: Resultssupporting

confidence: 75%

A New Resistance Gene, linB , Conferring Resistance to Lincosamides by Nucleotidylation in Enterococcus faecium HM1025

Bozdoğan

Berrezouga

Kuo³

et al. 1999

Antimicrob Agents Chemother

160

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Resistance to lincomycin and clindamycin in the clinical isolateEnterococcus faecium HM1025 is due to a ribosomal methylase encoded by an ermAM-like gene and the plasmid-mediated inactivation of these antibiotics. We have cloned and determined the nucleotide sequence of the gene responsible for the inactivation of lincosamides, linB. This gene encodes a 267-amino-acid lincosamide nucleotidyltransferase. The enzyme catalyzes 3-(5′-adenylation) (the adenylation of the hydroxyl group in position 3 of the molecules) of lincomycin and clindamycin. Expression oflinB was observed in both Escherichia coli andStaphylococcus aureus. The deduced amino acid sequence of the enzyme did not display any significant homology with staphylococcal nucleotidyltransferases encoded by linA andlinA′ genes. Sequences homologous to linB were found in 14 other clinical isolates of E. faecium, indicating the spread of the resistance trait in this species.

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Section: Resultssupporting

confidence: 75%

A New Resistance Gene, linB , Conferring Resistance to Lincosamides by Nucleotidylation in Enterococcus faecium HM1025

Bozdoğan

Berrezouga

Kuo³

et al. 1999

Antimicrob Agents Chemother

160

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“…Yet, to date there has been no detection of a Streptomyces lincolnensis -derived Lnu enzyme, or O -nucleotidylylation inactivation of lincosamides in this antibiotic producer. However, the presence of LCM O -NTase in the other Streptomyces species such as S. coelicolor has been reported [23]. Our genomic analysis also identified such enzymes, including the S. coelicolor gene with GenBank accession number NP_624450 (gi 21218671 in Fig.…”

Section: Discussionmentioning

confidence: 68%

Structural and Functional Plasticity of Antibiotic Resistance Nucleotidylyltransferases Revealed by Molecular Characterization of Lincosamide Nucleotidylyltransferases Lnu(A) and Lnu(D)

Stogios

Evdokimova

Morar

et al. 2015

Journal of Molecular Biology

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One of the main mechanisms of resistance to lincosamide and aminoglycoside antibiotics is their inactivation by O-nucleotidylyltransferases (NTases). Significant sequence variation of lincomycin nucleotidylyltransferase (Lnu) and aminoglycoside nucleotidylyltransferase (ANT) enzymes plus lack of detailed information about the molecular basis for specificity of these enzymes toward chemically distinct antibiotic scaffolds hinders development of a general strategy to curb this resistance mechanism. We conducted an extensive sequence analysis identifying 129 putative antibiotic NTases constituting six distinct subfamilies represented by Lnu(A), (B), (C), (D), (F)/(G) plus ANT(2″) enzymes. Since only the Lnu(B) enzyme has been previously studied in detail, we biochemically characterized the Lnu(A) and Lnu(D) enzymes, with the former representing the most sequence-distinct Lnu ortholog. We also determined the crystal structure of the Lnu(A) enzyme in complex with a lincosamide. These data suggested that while sharing the N-terminal nucleotidylyltransferase domain (NTD), the groups of antibiotic NTases feature structurally distinct C-terminal domains (CTD) adapted to accommodate antibiotics. Comparative structural analysis among antibiotic NTases rationalized their specificity toward lincosamides vs. aminoglycosides through active site plasticity, which allows retention of general catalytic activity, while accepting alterations at multiple, specific positions contributed by both domains. Based on this structural analysis, we suggest that antibiotic NTases evolved from an ancestral nucleotidylyltransferase along independent paths according to the identified groups, characterized by structural changes in the active site and recruitment of structurally-diverse CTDs. These data show the complexity of enzyme-driven antibiotic resistance and provides a basis for broadly-active inhibitors by identifying the key unifying features of antibiotic NTases.

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“…The members in cluster C are aminoglycoside 2”-phosphotransferases and stem from Gram-positive bacteria. No report has been published on the involvement of nucleotidyltransferase in the self-resistance in Streptomyces [80,86], although lincosaminide and muraymycin nucleotidyltransferases have been reported [87,88].…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Comparison of Antibiotic Resistance Mechanisms in Antibiotic-Producing and Pathogenic Bacteria

Ogawara

2019

Molecules

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Antibiotic resistance poses a tremendous threat to human health. To overcome this problem, it is essential to know the mechanism of antibiotic resistance in antibiotic-producing and pathogenic bacteria. This paper deals with this problem from four points of view. First, the antibiotic resistance genes in producers are discussed related to their biosynthesis. Most resistance genes are present within the biosynthetic gene clusters, but some genes such as paromomycin acetyltransferases are located far outside the gene cluster. Second, when the antibiotic resistance genes in pathogens are compared with those in the producers, resistance mechanisms have dependency on antibiotic classes, and, in addition, new types of resistance mechanisms such as Eis aminoglycoside acetyltransferase and self-sacrifice proteins in enediyne antibiotics emerge in pathogens. Third, the relationships of the resistance genes between producers and pathogens are reevaluated at their amino acid sequence as well as nucleotide sequence levels. Pathogenic bacteria possess other resistance mechanisms than those in antibiotic producers. In addition, resistance mechanisms are little different between early stage of antibiotic use and the present time, e.g., β-lactam resistance in Staphylococcus aureus. Lastly, guanine + cytosine (GC) barrier in gene transfer to pathogenic bacteria is considered. Now, the resistance genes constitute resistome composed of complicated mixture from divergent environments.

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Purification of lincosaminide O-nucleotidyltransferase from Streptomyces coelicolor Mueller.

Cited by 6 publications

References 11 publications

A New Resistance Gene, linB , Conferring Resistance to Lincosamides by Nucleotidylation in Enterococcus faecium HM1025

A New Resistance Gene, linB , Conferring Resistance to Lincosamides by Nucleotidylation in Enterococcus faecium HM1025

Structural and Functional Plasticity of Antibiotic Resistance Nucleotidylyltransferases Revealed by Molecular Characterization of Lincosamide Nucleotidylyltransferases Lnu(A) and Lnu(D)

Comparison of Antibiotic Resistance Mechanisms in Antibiotic-Producing and Pathogenic Bacteria

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