Identification and characterization of the anti-methicillin-resistant Staphylococcus aureus WAP-8294A2 biosynthetic gene cluster from Lysobacter enzymogenes OH11

Wei Zhang, Yaoyao Li, Guoliang Qian, Yan Wang, Haotong Chen, Yue Zhong Li, Fengquan Liu, Yuemao Shen, Liangcheng Du

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Lysobactor enzymogenes strain OH11 is an emerging biological control agent of fungal and bacterial diseases. We recently completed its genome sequence and found it contains a large number of gene clusters putatively responsible for the biosynthesis of nonribosomal peptides and polyketides, including the previously identified antifungal dihydromaltophilin (HSAF). One of the gene clusters contains two huge open reading frames, together encoding 12 modules of nonribosomal peptide synthetases (NRPS). Gene disruption of one of the NRPS led to the disappearance of a metabolite produced in the wild type and the elimination of its antibacterial activity. The metabolite and antibacterial activity were also affected by the disruption of some of the flanking genes. We subsequently isolated this metabolite and subjected it to spectroscopic analysis. The mass spectrometry and nuclear magnetic resonance data showed that its chemical structure is identical to WAP-8294A2, a cyclic lipodepsipeptide with potent antimethicillin- resistant Staphylococcus aureus (MRSA) activity and currently in phase I/II clinical trials. The WAP-8294A2 biosynthetic genes had not been described previously. So far, the Gram-positive Streptomyces have been the primary source of anti-infectives. Lysobacter are Gram-negative soil/water bacteria that are genetically amendable and have not been well exploited. The WAP-8294A2 synthetase represents one of the largest NRPS complexes, consisting of 45 functional domains. The identification of these genes sets the foundation for the study of the WAP-8294A2 biosynthetic mechanism and opens the door for producing new anti-MRSA antibiotics through biosynthetic engineering in this new source of Lysobacter.

Original languageEnglish (US)
Pages (from-to)5581-5589
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number12
DOIs
StatePublished - Dec 1 2011

Fingerprint

Lysobacter
Peptide Synthases
Methicillin-Resistant Staphylococcus aureus
Multigene Family
Nucleic Acid-Independent Peptide Biosynthesis
Genes
Biological Control Agents
Polyketides
Phase II Clinical Trials
Clinical Trials, Phase I
Mycoses
Streptomyces
Ligases
Open Reading Frames
Staphylococcus aureus
Mass Spectrometry
Magnetic Resonance Spectroscopy
Soil
Genome
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Identification and characterization of the anti-methicillin-resistant Staphylococcus aureus WAP-8294A2 biosynthetic gene cluster from Lysobacter enzymogenes OH11. / Zhang, Wei; Li, Yaoyao; Qian, Guoliang; Wang, Yan; Chen, Haotong; Li, Yue Zhong; Liu, Fengquan; Shen, Yuemao; Du, Liangcheng.

In: Antimicrobial Agents and Chemotherapy, Vol. 55, No. 12, 01.12.2011, p. 5581-5589.

Research output: Contribution to journalArticle

Zhang, Wei ; Li, Yaoyao ; Qian, Guoliang ; Wang, Yan ; Chen, Haotong ; Li, Yue Zhong ; Liu, Fengquan ; Shen, Yuemao ; Du, Liangcheng. / Identification and characterization of the anti-methicillin-resistant Staphylococcus aureus WAP-8294A2 biosynthetic gene cluster from Lysobacter enzymogenes OH11. In: Antimicrobial Agents and Chemotherapy. 2011 ; Vol. 55, No. 12. pp. 5581-5589.
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AU - Wang, Yan

AU - Chen, Haotong

AU - Li, Yue Zhong

AU - Liu, Fengquan

AU - Shen, Yuemao

AU - Du, Liangcheng

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