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Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials.

Publication ,  Journal Article
Hoque, J; Adhikary, U; Yadav, V; Samaddar, S; Konai, MM; Prakash, RG; Paramanandham, K; Shome, BR; Sanyal, K; Haldar, J
Published in: Molecular pharmaceutics
October 2016

The continuous rise of antimicrobial resistance and the dearth of new antibiotics in the clinical pipeline raise an urgent call for the development of potent antimicrobial agents. Cationic chitosan derivatives, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chlorides (HTCC), have been widely studied as potent antibacterial agents. However, their systemic structure-activity relationship, activity toward drug-resistant bacteria and fungi, and mode of action are very rare. Moreover, toxicity and efficacy of these polymers under in vivo conditions are yet to be established. Herein, we investigated antibacterial and antifungal efficacies of the HTCC polymers against multidrug resistant bacteria including clinical isolates and pathogenic fungi, studied their mechanism of action, and evaluated cytotoxic and antimicrobial activities in vitro and in vivo. The polymers were found to be active against both bacteria and fungi (MIC = 125-250 μg/mL) and displayed rapid microbicidal kinetics, killing pathogens within 60-120 min. Moreover, the polymers were shown to target both bacterial and fungal cell membrane leading to membrane disruption and found to be effective in hindering bacterial resistance development. Importantly, very low toxicity toward human erythrocytes (HC50 = >10000 μg/mL) and embryo kidney cells were observed for the cationic polymers in vitro. Further, no inflammation toward skin tissue was observed in vivo for the most active polymer even at 200 mg/kg when applied on the mice skin. In a murine model of superficial skin infection, the polymer showed significant reduction of methicillin-resistant Staphylococcus aureus (MRSA) burden (3.2 log MRSA reduction at 100 mg/kg) with no to minimal inflammation. Taken together, these selectively active polymers show promise to be used as potent antimicrobial agents in topical and other infections.

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Published In

Molecular pharmaceutics

DOI

EISSN

1543-8392

ISSN

1543-8384

Publication Date

October 2016

Volume

13

Issue

10

Start / End Page

3578 / 3589

Related Subject Headings

  • Structure-Activity Relationship
  • Staphylococcal Skin Infections
  • Quaternary Ammonium Compounds
  • Pharmacology & Pharmacy
  • Microbial Sensitivity Tests
  • Mice, Inbred BALB C
  • Mice
  • Methicillin-Resistant Staphylococcus aureus
  • Humans
  • Female
 

Citation

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Hoque, J., Adhikary, U., Yadav, V., Samaddar, S., Konai, M. M., Prakash, R. G., … Haldar, J. (2016). Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials. Molecular Pharmaceutics, 13(10), 3578–3589. https://doi.org/10.1021/acs.molpharmaceut.6b00764
Hoque, Jiaul, Utsarga Adhikary, Vikas Yadav, Sandip Samaddar, Mohini Mohan Konai, Relekar Gnaneshwar Prakash, Krishnamoorthy Paramanandham, Bibek R. Shome, Kaustuv Sanyal, and Jayanta Haldar. “Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials.Molecular Pharmaceutics 13, no. 10 (October 2016): 3578–89. https://doi.org/10.1021/acs.molpharmaceut.6b00764.
Hoque J, Adhikary U, Yadav V, Samaddar S, Konai MM, Prakash RG, et al. Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials. Molecular pharmaceutics. 2016 Oct;13(10):3578–89.
Hoque, Jiaul, et al. “Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials.Molecular Pharmaceutics, vol. 13, no. 10, Oct. 2016, pp. 3578–89. Epmc, doi:10.1021/acs.molpharmaceut.6b00764.
Hoque J, Adhikary U, Yadav V, Samaddar S, Konai MM, Prakash RG, Paramanandham K, Shome BR, Sanyal K, Haldar J. Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials. Molecular pharmaceutics. 2016 Oct;13(10):3578–3589.
Journal cover image

Published In

Molecular pharmaceutics

DOI

EISSN

1543-8392

ISSN

1543-8384

Publication Date

October 2016

Volume

13

Issue

10

Start / End Page

3578 / 3589

Related Subject Headings

  • Structure-Activity Relationship
  • Staphylococcal Skin Infections
  • Quaternary Ammonium Compounds
  • Pharmacology & Pharmacy
  • Microbial Sensitivity Tests
  • Mice, Inbred BALB C
  • Mice
  • Methicillin-Resistant Staphylococcus aureus
  • Humans
  • Female