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 Table of Contents    
EDITORIAL
Year : 2018  |  Volume : 50  |  Issue : 1  |  Page : 1-3
 

Specifically targeted antimicrobial peptides: A new and promising avenue in selective antimicrobial therapy


Department of Pharmacology, PGIMER, Chandigarh, India

Date of Submission24-Apr-2018
Date of Acceptance27-Apr-2018
Date of Web Publication30-Apr-2018

Correspondence Address:
Bikash Medhi
Research Block B, 4th Floor, Room No. 4043, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_218_18

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How to cite this article:
Sarma P, Mahendiratta S, Prakash A, Medhi B. Specifically targeted antimicrobial peptides: A new and promising avenue in selective antimicrobial therapy. Indian J Pharmacol 2018;50:1-3

How to cite this URL:
Sarma P, Mahendiratta S, Prakash A, Medhi B. Specifically targeted antimicrobial peptides: A new and promising avenue in selective antimicrobial therapy. Indian J Pharmacol [serial online] 2018 [cited 2018 May 27];50:1-3. Available from: http://www.ijp-online.com/text.asp?2018/50/1/1/231475




The human body is colonized by more than 100 trillion microbes, which comprise the human microbiome.[1] The microbiome consists of more than 1000 species of bacteria, and Bacteroidetes and Firmicutes were the dominant phyla. Diversity of gut microbiota is quite huge compared to other body sites, and variation is seen in the gut microbiota constituents even among healthy adult humans.[2] The bacterial mass comprises only 1%–3% of the human body mass. This is because of their small size. Although the comparative mass is less, the number of microbes is 10 times more than the number of human cells.[3]

The microbiota shares a diverse range of functions, e.g., metabolic functions, host immune system development, protect against pathogens, production of vitamins, digestion of food, and produce chemicals to fight off disease-causing pathogens, and thus plays an important role in maintaining human health and has tremendous impact on our body physiology, both in health and in disease conditions.[1],[2],[3] Bidirectional signaling between the gastrointestinal tract and the brain by means of the “vagus” comprises the “gut–brain axis.” This axis is vital for maintaining body homeostasis. This axis is altered in many metabolic and mental dysfunctions/disorders.[4]

The normal microbial flora is also responsible for the “colonization resistance” phenomenon, i.e., the normal commensal bacteria can prevent colonization of disease-causing pathogens. The normal microbial flora occupies the niche, causing limitation of the nutrients and available space, and thus prevents colonization by foreign pathogens. Again, many commensal colonizers produce inhibitory substance against pathogenic species. Many streptococcal commensals in the oral cavity synthesize inhibitory substance, to prevent colonization by other colonizers, e.g., production of hydrogen peroxide by Streptococcus sanguinis. Oral microbiome also has role in maintaining the level of nitrite and thus possess indirect role in maintaining cardiovascular health.[1]

Data from human microbiome project have shown that alteration in the normal microbiota is associated with many diseases, including obesity, periodontitis, inflammatory bowel disease, irritable bowel syndrome, diabetes, cancer, rheumatoid arthritis, Alzheimer's disease, and  Parkinsonism More Details's disease.[2],[5]

Alteration of this microbiota is associated with disease state; the biggest example is antibiotic-associated diarrhea. The organism responsible is Clostridium difficile, and broad-spectrum penicillins, clindamycin, and cephalosporins are the most common culprits. Almost 5%–10% of patients on ampicillin, 15%–20% of patients on cefixime, and 10%–25% of patients receiving amoxicillin-clavulanic acid complain of diarrhea at different stages of their treatment. Antibiotics reaching colon in higher amounts (e.g., poorly absorbed in the upper part of intestine) are the frequent culprit. However, antibiotics reaching intestine through bile duct are also equally responsible. Use of these agents disrupts the normal commensal flora and subsequent overgrowth of C. difficile and development of symptoms, e.g., diarrhea, fever, and colitis.[6]

Here comes the importance of development of highly selective antimicrobials, which kills the targeted organism selectively and at the same time does not alter the prevalent microbial flora.


  Specifically Targeted Antimicrobial Peptides Top


STAMPs stand for “specifically targeted antimicrobial peptides,” which are designed to selectively target and kill specific pathogens and at the same time without affecting the normal microbial flora. Eckert et al.(2006) were a pioneer in this field to propose the ideas of developing STAMPs to combat antimicrobial resistance with minimal or no impact on the normal commensals.[7] STAMPs typically consist of two regions, targeting and killing regions, which are independent functionally and joined by a linker. The targeting region enhances the activity of the peptide molecule by enhancing binding to the target pathogen with the help of specific determinants and thus leads to accumulation of the killing moiety in the selective pathogens.[8]


  Specifically Targeted Antimicrobial Peptide Against Streptococcus Mutans Top


Huo et al. have developed and evaluated 11 STAMPs and also evaluated its effect on the growth of Streptococcus mutans biofilm, among which five STAMPs, i.e., C8H, C11H, C12H, C13H, and C14H, significantly inhibited the growth of biofilm of S. mutans, without significant effect on biofilm of Streptococcus gordonii and S. sanguinis biofilm. Among the STAMPs evaluated, highest efficacy was shown by C11H and C12H. The STAMPs showed antibacterial activity against S. mutans grown in planktonic or biofilm states, without significant alteration of oral streptococci and multi-species biofilm.[9]

Another significant advancement in the selective targeting of S. mutans is the development of C16G2, the targeting region of which is S. mutans competence stimulation peptide and the killing component is G2, which is a broad-spectrum antimicrobial peptide. High selectivity of C16G2 toward S. mutans was demonstrated in vitro in both mono-species and multi-species cultures (saliva-derived) spiked with S. mutans. After 24 h, it was seen that bacterial species with a symbiotic relation with S. mutans also reduced significantly, and on the contrary, health-associated streptococci became the dominant species.[10] This implies the therapeutic potential of the compound.


  Multiple-Headed Specifically Targeted Antimicrobial Peptide: Targeting Pseudomonas Aeruginosaand Streptococcus Mutants Together Top


The conventional STAMPs usually contain one targeting region and one killing agent. As an extension of this concept, He et al. developed a STAMP with multiple-targeting regions, targeting two different bacteria. They have developed a multiple-headed STAMP named as M8(KH)-20, in which multiple-targeting heads were attached to an AMP using a lysine residue branch point. This peptide demonstrated specific activity against Pseudomonas aeruginosa and Streptococcus mutants in vitro, with little effect on other species.[11]

Another antimicrobial peptide “novispirin G10” is converted to a STAMP named as “G10KHc.” G10KHc had enhanced ability to kill P. aeruginosa in the clinical isolates. Efficacy of G10KHc was similar and synergistic action was noted when G10KHc was combined with neosporin.[7]


  Specifically Targeted Antimicrobial Peptide Targeting Methicillin-Resistant Staphylococcus aureus Top


Agplectasin is a STAMP created by fusing AgrD1 pheromone to the N-terminal end of plectasin. It is especially effective against methicillin-resistant S. aureus. Mao et al. developed recombinant Agplectasin. This recombinant form also showed strong cidal action toward S. aureus, but other components of normal flora, e.g., Staphylococcus epidermidis, remained unaffected, which highlighted its high specificity.[12]


  Current Status in Clinical Phase Top


Although many of the STAMPs showed promising activity in vitro and in preclinical studies, till now, only very few have reached the clinical evaluation stage. Sullivan et al. evaluated the efficacy of C16G2 mouth rinse (0.04% w/v) for targeted elimination of S. mutans and prevention of demineralization in both in vitro and in clinical settings (in an intraoral remineralization/demineralization model). Single treatment with C16G2 led to selective elimination of S. mutans both from saliva and plaque, which resulted in a healthy plaque, without disturbing the remaining microbial flora. This healthy flora even resisted S. mutans growth in spite of repeated sucrose challenges. This resulted in a healthy plaque, which showed a significant resistance toward enamel demineralization.[13] Currently, C16G2 has completed phase 2 clinical trials.[14]


  Conclusion and Future Perspective Top


Alteration of the normal microbiome results in dysbiosis and subsequent disease conditions or altered pathophysiology. Development of STAMPs is a very significant advancement in this regard. Although lots of STAMPs showed promising effects, very few have reached the clinical evaluation stages. We need more focused research (both preclinical and clinical) in these areas for better development of microbiome-friendly antimicrobials with clinical utility.



 
  References Top

1.
Stone VN, Xu P. Targeted antimicrobial therapy in the microbiome era. Mol Oral Microbiol 2017;32:446-54.  Back to cited text no. 1
    
2.
Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol 2015;31:69-75.  Back to cited text no. 2
    
3.
About the Human Microbiome. NIH Human Microbiome Project – About the Human Microbiome. Available from: https://www.hmpdacc.org/hmp/overview/. [Last accessed on 2018 Apr 10].  Back to cited text no. 3
    
4.
Montiel-Castro AJ, González-Cervantes RM, Bravo-Ruiseco G, Pacheco-López G. The microbiota-gut-brain axis: Neurobehavioral correlates, health and sociality. Front Integr Neurosci 2013;7:70.  Back to cited text no. 4
    
5.
Jorth P, Turner KH, Gumus P, Nizam N, Buduneli N, Whiteley M, et al. Metatranscriptomics of the human oral microbiome during health and disease. MBio 2014;5:e01012-14.  Back to cited text no. 5
    
6.
Coté GA, Buchman AL. Antibiotic-associated diarrhoea. Expert Opin Drug Saf 2006;5:361-72.  Back to cited text no. 6
    
7.
Eckert R, Brady KM, Greenberg EP, Qi F, Yarbrough DK, He J, et al. Enhancement of antimicrobial activity against Pseudomonas aeruginosa by coadministration of G10KHc and tobramycin. Antimicrob Agents Chemother 2006;50:3833-8.  Back to cited text no. 7
    
8.
He J, Yarbrough DK, Kreth J, Anderson MH, Shi W, Eckert R, et al. Systematic approach to optimizing specifically targeted antimicrobial peptides against Streptococcus mutans. Antimicrob Agents Chemother 2010;54:2143-51.  Back to cited text no. 8
    
9.
Huo L, Huang X, Ling J, Liu H, Liu J. Selective activities of STAMPs against Streptococcus mutans. Exp Ther Med 2018;15:1886-93.  Back to cited text no. 9
    
10.
Guo L, McLean JS, Yang Y, Eckert R, Kaplan CW, Kyme P, et al. Precision-guided antimicrobial peptide as a targeted modulator of human microbial ecology. Proc Natl Acad Sci U S A 2015;112:7569-74.  Back to cited text no. 10
    
11.
He J, Anderson MH, Shi W, Eckert R. Design and activity of a 'dual-targeted' antimicrobial peptide. Int J Antimicrob Agents 2009;33:532-7.  Back to cited text no. 11
    
12.
Mao R, Teng D, Wang X, Xi D, Zhang Y, Hu X, et al. Design, expression, and characterization of a novel targeted plectasin against methicillin-resistant Staphylococcus aureus. Appl Microbiol Biotechnol 2013;97:3991-4002.  Back to cited text no. 12
    
13.
Sullivan R, Santarpia P, Lavender S, Gittins E, Liu Z, Anderson MH, et al. Clinical efficacy of a specifically targeted antimicrobial peptide mouth rinse: Targeted elimination of Streptococcus mutans and prevention of demineralization. Caries Res 2011;45:415-28.  Back to cited text no. 13
    
14.
Clinicaltrials.gov. Search of: C16G2-List Results. Search of: C16G2-List Results-ClinicalTrialsgov. Available from: https://www.clinicaltrials.gov/ct2/results?cond=C16G2 and term=& cntry=&state=&city=&dist=. [Last accessed on 2018 Apr 19].  Back to cited text no. 14
    




 

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