NCBI RefSeq’s Antimicrobial Peptide Indexed Field: Facilitating Novel Antibiotic Discovery


This blog post is aimed toward biomedical researchers.

Antibiotic-resistant bacterial infections account for the deaths of tens of thousands of Americans every year. Over the past twenty years, these difficult to treat infections have become more common. Since traditional antibiotics are ineffective in these cases, biomedical researchers are looking for alternatives. NCBI’s RefSeq project has created a new indexed field, “Protein has antimicrobial activity [prop]“, to assist in this search by retrieving useful sequence annotation showing naturally occurring antimicrobial peptides, or AMPs.

Antimicrobial peptides are naturally occurring peptides from a diverse array of species that are a part of an organism’s innate immune system. The RefSeq team recently gathered a list of over 130 human genes encoding one or more experimentally proven AMPs. These peptides are typically less than 100 amino acids and can display bactericidal, antiviral, antifungal, and even antitumor activities, with a specific AMP usually having a subset of these activities. AMPs may be a suitable alternative to traditional antibiotics because they work quickly, efficiently, and tend to have broad spectrum activity. Moreover, since they are naturally-occurring, AMPs are less likely than other compounds to be toxic to host cells or to give rise to AMP-resistant bacterial strains.

This list was culled from several different public databases (APD2, CAMP, YADAMP, and LAMP) as well as from a handful of publications (PMIDs: 24828484, 24862593, 23935642, 24965684, and 22074402). Most of these AMPs had not been identified in the RefSeq database, and none of the AMP databases has determined from which genes the individual AMPs were derived. To document the transcript(s) and location encoding each AMP, the gene encoding each AMP was determined. Manual annotation on RefSeq records was done according to the following guidelines (the example below comes from the ADM precursor [Homo sapiens] record):

1. A publication describing the antimicrobial activity of the peptide will be included in the publications section of the RefSeq record, along with a GeneRIF describing the specific activity of the AMP.

REFERENCE   6  (residues 1 to 185)
  AUTHORS   Allaker RP, Zihni C and Kapas S.
  TITLE     An investigation into the antimicrobial effects of
            adrenomedullin on members of the skin, oral,
            respiratory tract and gut microflora
  JOURNAL   FEMS Immunol. Med. Microbiol. 23 (4), 289-293 (1999)
   PUBMED 10225288
  REMARK    GeneRIF: Adrenomedullin has broad bacteriocidal
            activity against gram-positive and gram-negative
            bacteria.

2. The RefSeq record will have a “REVIEWED” status and will contain a summary that includes the antimicrobial activity of the encoded AMP. Also, the phrase “Protein has antimicrobial activity” and a supporting PubMed ID will be included in the RefSeq attribute COMMENT block.

COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI
            staff. The reference sequence was derived from
            HY105655.1, D14874.1 and BQ021632.1.

            Summary: The protein encoded by this gene is a
            preprohormone which is cleaved to form two biologically
            active peptides, adrenomedullin and proadrenomedullin N
            -terminal 20 peptide. Adrenomedullin is a 52 aa peptide
            with several functions, including vasodilation,
            regulation of hormone secretion, promotion of
            angiogenesis, and antimicrobial activity. The
            antimicrobial activity is antibacterial, as the peptide
            has been shown to kill E. coli and S. aureus at low
            concentration. [provided by RefSeq, Aug 2014].
            Publication Note: This RefSeq record includes a subset
            of the publications that are available for this gene.
            Please see the Gene record to access additional
            publications.

            ##RefSeq-Attributes-START##
            Protein has antimicrobial activity :: PMID: 10225288
            ##RefSeq-Attributes-END##

3. The nucleotide and amino acid range of the peptide will be annotated on the RefSeq record and will be tagged with /experiment=”DESCRIPTION:antimicrobial peptide [PMID:xxxxxxxx]”.

mat_peptide     95..146
                /product="adrenomedullin"
                /experiment="DESCRIPTION:antimicrobial peptide
                [PMID: 10225288]"
                /calculated_mol_wt=6032

Finally, to access all of the records for which RefSeq has curated AMPs, go to either our Nucleotide or Protein resources and search using “Protein has antimicrobial activity”[prop]. Currently, this search will find 191 RefSeq records (NM or NPs), which is greater than the 130+ genes represented because some genes have several transcript variants. For example, there are four PRG2 (GeneID 5533) variants that encode AMPs, and all four are found by the “Protein has antimicrobial activity”[prop] search.

Reference list:

  • González-Navajas JM, Corr MP, Raz E. (2014) The immediate protective response to microbial challenge. Eur.J.Immunol. Sep; 44(9):2536-49. PMID: 24965684.
  • Pasupuleti M, Scmidtchen A, Malmsten M. (2012) Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol. Jun;32(2):143-71. PMID: 22074402.
  • Pushpanathan M, Gunasekaran P, Rajendhran J. (2013) Antimicrobial peptides: versatile biological properties. Int J Pept. PMID: 23935642.
  • Uppu DS, Ghosh C, Haldar. (2015) Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to antibiotic therapy? J. Microb. Pathog. Feb 9;80C:7-13. PMID: 25677832.
  • van’t Hof W, Veerman EC, Nieuw Amerongen AV, Ligtenberg AJ. (2014) Antimicrobial defense systems in saliva. Monogr Oral Sci. 24:40-51. PMID: 24862593.
  • Wang G. (2014) Human antimicrobial peptides and proteins. Pharmaceuticals (Basel). May 13;7(5):545-94. PMID: 24828484.

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