Selectively targeted antimicrobial peptides and the use thereof
Inventors
Eckert, Randal H. • Yarbrough, Daniel K. • Shi, Wenyuan • Anderson, Maxwell H. • Qi, Fengxia • He, Jian • McHardy, Ian H.
Assignees
University of California San Diego UCSD • C3J Therapeutics Inc
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Publication Number
US-8680058-B2
Publication Date
2014-03-25
Expiration Date
Abstract
The present invention relates to targeting peptides capable of specifically binding to microbial organisms (e.g., P. aeruginosa or S. mutans), antimicrobial peptides having antimicrobial activities, and specifically/selectively targeted antimicrobial peptides (STAMPs). In addition, the present invention provides methods of selectively killing or inhibiting microbial organisms by using the peptides or compositions provided by the present invention.
Core Innovation
The patent describes selectively/specifically targeted antimicrobial peptides (STAMPs) that include a microbial-targeting peptide linked to an antimicrobial peptide. The targeting peptide is based on fragments of the competence stimulating peptide (CSP) to bind Streptococcus mutans, with the CSP fragment ranging in length from 8 to 20 amino acids, and the targeting peptide is attached directly to an antimicrobial peptide or via defined linker peptides.
The antimicrobial component is configured as an antimicrobial peptide construct, including novispirin G10 derivatives and related antimicrobial peptides. Exemplary constructs include Streptococcus mutans-targeting CSP-derived domains, including C16, M8, and CSP fragment regions, linked to novispirin G10 derivative embodiments such as G2, along with defined linker sequences and optional D-amino acid enantiomers.
The patent reports selectivity and activity in single- and multi-species oral biofilms and describes a mechanism that includes ComD-independent binding. It also describes retaining selectivity when CSP/CSP-fragment-guided STAMPs are paired with alternative antimicrobial peptides, and it describes targeted antimicrobial constructs for killing Streptococcus mutans and other target microbes, including a combination construct involving a Pseudomonas aeruginosa STAMP and tobramycin, with enhanced or synergistic killing in planktonic cultures and biofilms.
Claims Coverage
The independent claims cover a targeting construct composition and a method for selectively killing Streptococcus mutans using that construct. Across the independent claims, the inventive features focus on CSP fragment-based Streptococcus mutans targeting, 8 to 20 amino acids in length, and attachment to an antimicrobial peptide and/or a detectable agent.
CSP fragment Streptococcus mutans targeting attached to a detectable agent
A composition including a targeting peptide that binds Streptococcus mutans, where the targeting peptide comprises a fragment of the competence stimulating peptide (CSP) ranging in length from 8 to 20 amino acids, and where the targeting peptide is attached to a detectable agent.
CSP fragment Streptococcus mutans targeting attached to an antimicrobial peptide
A composition including a targeting peptide that binds Streptococcus mutans attached to an antimicrobial peptide, where the amino acid sequence of the targeting peptide comprises a fragment of the competence stimulating peptide (CSP) ranging in length from 8 to 20 amino acids.
Selective killing of Streptococcus mutans using a CSP fragment targeting antimicrobial construct
A method of selectively killing Streptococcus mutans by contacting Streptococcus mutans with an amount of a construct effective to kill Streptococcus mutans, where the construct comprises a targeting peptide that binds Streptococcus mutans attached to an antimicrobial peptide, and where the targeting peptide comprises a fragment of the competence stimulating peptide (CSP) ranging in length from 8 to 20 amino acids.
Overall, the claim coverage is centered on CSP fragment-derived targeting peptides that bind Streptococcus mutans and are attached to either a detectable agent and/or an antimicrobial peptide, with a method claim directed to selectively killing Streptococcus mutans using an effective amount of the targeting antimicrobial construct.
Stated Advantages
Selectively killing Streptococcus mutans.
Enhanced selectivity for killing Streptococcus mutans versus non-target oral streptococci.
Retention of activity with short exposure in single- and multi-species biofilms.
ComD-independent binding mechanism for the CSP-guided constructs.
Retained selectivity when paired with alternative antimicrobial peptides.
Enhanced or synergistic killing when a Pseudomonas aeruginosa STAMP construct is combined with tobramycin in planktonic cultures and biofilms.
Documented Applications
Killing and inhibiting target microbes, including Streptococcus mutans, in subjects and in biofilms.
Targeted antimicrobial constructs for use in oral biofilms, including single- and multi-species biofilms.
Combinational therapeutic use for Pseudomonas aeruginosa killing in planktonic cultures and biofilms with tobramycin.
Diagnostic/detectable-agent targeting concepts using a targeting peptide linked to a detectable agent, including radioisotopes, fluorescent agents, or enzyme-substrate systems.
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