Novel Synthetic Antimicrobial Peptides against
            <i>Streptococcus mutans</i>

He, Jian; Eckert, Randal; Pharm, Thanh; Simanian, Maurice D.; Hu, Chuhong; Yarbrough, Daniel K.; Qi, Fengxia; Anderson, Maxwell; Shi, Wenyuan

doi:10.1128/aac.01270-06

Cited by 58 publications

(43 citation statements)

References 42 publications

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“…We conjugated Sm6 with RWRWRWF(2C-4), FKKFWKWF RRF(B-33), IKQLLHFFQRF(B-38), RWRRLLKKLHHLLH (␣-11), and LQLLKQLLKLLKQF(␣-7) (attached at the C or N terminus), five AMPs selected from our previous studies (12), to construct library 2. The linkers selected to make a total of 40 STAMPs were L1, SGG (L6), L3, and LC (8-amino caprylic acid) ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Systematic Approach to Optimizing Specifically Targeted Antimicrobial Peptides against Streptococcus mutans

Yarbrough

Kreth

Anderson

et al. 2010

Antimicrob Agents Chemother

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Previously we reported a novel strategy of "targeted killing" through the design of narrow-spectrum molecules known as specifically targeted antimicrobial peptides (STAMPs) Construction of these molecules requires the identification and the subsequent utilization of two conjoined yet functionally independent peptide components: the targeting and killing regions. In this study, we sought to design and synthesize a large number of STAMPs targeting Streptococcus mutans, the primary etiologic agent of human dental caries, in order to identify candidate peptides with increased killing speed and selectivity compared with their unmodified precursor antimicrobial peptides (AMPs). We hypothesized that a combinatorial approach, utilizing a set number of AMP, targeting, and linker regions, would be an effective method for the identification of STAMPs with the desired level of activity. STAMPs composed of the Sm6 S. mutans binding peptide and the PL-135 AMP displayed selectivity at MICs after incubation for 18 to 24 h. A STAMP where PL-135 was replaced by the B-33 killing domain exhibited both selectivity and rapid killing within 1 min of exposure and displayed activity against multispecies biofilms grown in the presence of saliva. These results suggest that potent and selective STAMP molecules can be designed and improved via a tunable "buildingblock" approach.(Pathogenic microorganisms have been a continuous source of human suffering and mortality throughout the course of human history and have spurred the clinical development of novel therapeutics. Even today, the overall burden of infectious disease remains high, constituting a leading (and rising) cause of death worldwide (16,18). The conventional medical response to bacterial infections, administration of small-molecule antibiotics, has become less effective against emerging pathogens due to the evolution of drug resistance stemming in part from the misuse of antibiotics (13). Additionally, antibiotics and oral antiseptics currently in use to treat mucosal infections eliminate pathogens and bystander bacteria alike, an outcome that can be associated with negative clinical consequences (15, 17). Therefore, there is an unmet medical need to develop novel, narrow-spectrum therapeutics capable of maintaining the protective benefits of the normal microflora during treatment.Our strategy for creating novel, selective antibacterial agents is based on the addition of a targeting peptide to an existing broadspectrum antimicrobial peptide (AMP), thereby generating a specifically targeted antimicrobial peptide (STAMP) selective for a particular bacterial species or strain. A completed STAMP consists of conjoined but functionally independent targeting and killing regions, separated by a small flexible linker, all within a linear peptide sequence. The STAMP targeting region drives enhancement of antimicrobial activity by increasing binding to the surface of a targeted pathogen, utilizing specific determinants such as overall membrane hydrophobicity, charge, and/or pheromone recept...

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Section: Resultsmentioning

confidence: 99%

“…For peptides insoluble in aqueous solutions, stock solutions were prepared in 50% methanol and appropriate solvent controls were utilized. Cell growth was not affected by 5% (vol/vol) methanol, as described previously (12).…”

Section: Methodsmentioning

confidence: 99%

Systematic Approach to Optimizing Specifically Targeted Antimicrobial Peptides against Streptococcus mutans

Yarbrough

Kreth

Anderson

et al. 2010

Antimicrob Agents Chemother

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“…The differential bactericidal effects found between the VIP derivatives and native VIP could be due to the higher net positive charge and hydrophobicity of the former because both characteristics seem to be critical in the susceptibility of some Gram-positive bacteria, such as S. mutans, to many antimicrobial peptides (44). Because VIP51(6 -30) has a higher positive charge and ␣-helix percentage than VIP51, VIP51(6 -30) could interact better with S. mutans and cause its death at lower peptide concentrations.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of Stable Analogues of Vasoactive Intestinal Peptide against Pathogens

Campos‐Salinas

Cavazzuti

O’Valle³

et al. 2014

Journal of Biological Chemistry

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Background: Antimicrobial properties of the anti-inflammatory neuropeptide VIP are limited by its unstable nature. Results: The VIP derivatives protected against polymicrobial sepsis and cutaneous leishmaniasis by selectively killing pathogens through membrane-disrupting mechanisms. Conclusion: Modification of critical residues in the native VIP sequence generates stable peptides with potent antimicrobial activities in vitro and in vivo. Significance: This work indicates a molecular rationale for designing new agents against drug-resistant infectious diseases.

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“…To circumvent this problem, an innovative approach has recently been developed to design a new class of antimicrobials, called "specifically targeted antimicrobial peptides" (STAMPs), which selectively target a specific organism with little effect on the other members of the resident flora (7,10,26). The design of such target-specific AMPs requires the identification of two functionally independent peptide components, a killing moiety comprised of a nonspecific AMP that can rapidly kill bacterial cells and a targeting moiety consisting of an organism-specific, high-affinity binding peptide (7,26).…”

Section: Discussionmentioning

confidence: 99%

“…By taking advantage of our studies and those of others (7,10,26), we have designed several fusion peptides that consist of a short targeting domain of S. mutans CSP fused to a killing domain from a selected pleurocidin, NRC-4, via a small linker (7). In addition, the fusion peptides are amidated at their C termini to eliminate the end charge, since peptides amidated at their C termini frequently show better antimicrobial activities than their unamidated parent peptides (23,25).…”

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confidence: 99%

A Novel Target-Specific, Salt-Resistant Antimicrobial Peptide against the Cariogenic Pathogen Streptococcus mutans

Mai

Tian

Gallant

et al. 2011

Antimicrob Agents Chemother

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In this study, we constructed and evaluated a target-specific, salt-resistant antimicrobial peptide (AMP) that selectively targeted Streptococcus mutans, a leading cariogenic pathogen. The rationale for creating such a peptide was based on the addition of a targeting domain of S. mutans ComC signaling peptide pheromone (CSP) to a killing domain consisting of a portion of the marine-derived, broad-spectrum AMP pleurocidin to generate a target-specific AMP. Here, we report the results of our assessment of such fusion peptides against S. mutans and two closely related species. The results showed that nearly 95% of S. mutans cells lost viability following exposure to fusion peptide IMB-2 (5.65 M) for 15 min. In contrast, only 20% of S. sanguinis or S. gordonii cells were killed following the same exposure. Similar results were also observed in dual-species mixed cultures of S. mutans with S. sanguinis or S. gordonii. The peptide-guided killing was further confirmed in S. mutans biofilms and was shown to be dose dependent. An S. mutans mutant defective in the CSP receptor retained 60% survival following exposure to IMB-2, suggesting that the targeted peptide predominantly bound to the CSP receptor to mediate killing in the wild-type strain. Our work confirmed that IMB-2 retained its activity in the presence of physiological or higher salt concentrations. In particular, the fusion peptide showed a synergistic killing effect on S. mutans with a preventive dose of NaF. In addition, IMB-2 was relatively stable in the presence of saliva containing 1 mM EDTA and did not cause any hemolysis. We also found that replacement of serine-14 by histidine improved its activity at lower pH. Because of its effectiveness, salt resistance, and minimal toxicity to host cells, this novel target-specific peptide shows promise for future development as an anticaries agent.

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Novel Synthetic Antimicrobial Peptides against Streptococcus mutans

Cited by 58 publications

References 42 publications

Systematic Approach to Optimizing Specifically Targeted Antimicrobial Peptides against Streptococcus mutans

Systematic Approach to Optimizing Specifically Targeted Antimicrobial Peptides against Streptococcus mutans

Therapeutic Efficacy of Stable Analogues of Vasoactive Intestinal Peptide against Pathogens

A Novel Target-Specific, Salt-Resistant Antimicrobial Peptide against the Cariogenic Pathogen Streptococcus mutans

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