Download GREEN METHODS TO DELIVER AMINOGLYCOSIDE DRUGS

GREEN METHODS TO DELIVER AMINOGLYCOSIDE DRUGS
Aminoglycosides are sugar molecules, known as golden antibiotics for past 60 years.1 Currently more
than 20 aminoglycosides are used (e.g. Neomycin, Gentamicin, Tobramycin, Paromomycin, etc., Fig.
1) in clinical and veterinary practice to treat mostly life-threatening bacterial infections.2 In particular,
aminoglycosides are the second line drugs for Tuberculosis bacteria (TB).2 Recently, mechanism of
aminoglycoside action was demonstrated by Prof. Venkatraman Ramakrishnan, who has been awarded
noble prize for chemistry in 2009.3 To date, the extensive clinical applications of aminoglycosides are
limited due to two major reasons (i) inherent toxicity and (ii) less permeability to cell membranes.4
Figure 1. Common structures of aminoglycoside families
Green chemistry in pharmaceutical development often concern the synthesis of the active ingredient,
but green-chemistry techniques also can be applied to drug-product manufacturing, formulation
development, and drug delivery.5 Drugs with the ability to penetrate cell membranes, have much
stronger efficacy, however many drugs are do not do so. In order to compensate, drugs often need to
be administered in higher doses. Obviously, this increases toxicity and the possibility of bacteria and
other organisms mutating as the high doses make it easier for them to build resistance against drugs.
This leads to treatments becoming obsolete and the need for new medicines to be developed.5
Recently, many green drug delivery platforms have emerged and are present either in clinical use or in
an advanced clinical trial that overcomes permeability, toxicity and resistance issues while keeping
similar activity.6 One of such platforms namely Cochleates has been introduced as a novel lipid-based
green drug delivery system. Cochleates represent a powerful vaccine formulation and has many
advantages like non-toxic, non-infectious, non-inflammatory, biodegradable and stable. It has the
potential to deliver hydrophobic/charged hydrophilic drugs. They are stable phospholipid-calcium
precipitates comprised mainly of phosphatidylserine. They have defined multilayered structure
consisting of a continuous, solid, lipid bilayer sheet rolled up in a spiral, with no internal aqueous
space (Fig. 2).8
The concept of cochelates has been recently applied to amphotericin B which is a polyene antifungal
drug, often used intravenously for systemic fungal infections. Cochleate-Amphotericin B systems is
currently in advanced clinical trial for the treatment of fungal infections. Fungisome is a liposomal
complex of amphotericin B, and being the latest and cheapest addition to the lipid formulations of
amphotericin B, it has many advantages. It is marketed by Lifecare Innovations of India. Other
formulations include Amphotec (InterMune) and Abelcet (Enzon Pharmaceuticals). Abelcet is not a
liposomal preparation but rather a lipid complex preparation. 9ABELCET® consists of amphotericin B
complexed with two phospholipids in a 1:1 drug-to-lipid molar ratio. Ampholip is a lipid complex
formulation of amphotericin B marketed by Bharat Serums & Vaccines Ltd, Mumbai, India.7 All these
developments in green drug delivery platforms show Cochleate- Aminoglycosides as promising scope
in pharma industry.
Figure 2. Structures of cochleates
Objectives of Research proposal:
Main Goal: To develop green methods for delivering toxic aminoglycoside drugs. The specific aim is
"Synthesis, characterization and biological applications of Cochleate- Aminoglycosides complexes as
novel antibiotics against Multi Drug Resistance bacteria's (MDR) and Tuberculosis bacteria".
Rational behind the design:
Since cochleates are formed by ionic interaction between negatively charged liposomes and bivalent
cations, microencapsulation of cationic drugs such as aminoglycosides can be used as the bridging
agents for cochleation (Fig. 3). This new type of cochleate is inherent in the physicochemical
properties of metal ion‐bridged cochleates in terms of their conversion back to liposomes upon the
extraction of cation bridging agent and their ability to fuse with the cell membrane. These unique
properties will enable cochleates to deliver aminoglycoside antibiotics across the tissue membrane.8
Figure 3. Formation of Aminoglycosides-Cochleate complex.
Expected benefits by this study:
Aminoglycosides are very cheap and natural antibiotics that shows broad spectrum of activity against
Gram negative/positive bacteria's and mycobacterium (TB). It is only used for life-threatening
bacterial infections due to less permeability and toxicity. Aminoglycosides-Cochleate drug can
overcome the both permeability and toxicity issues, because, cochleate deliver the aminoglycosides
directly in to the cells. Thus, we need only small concentration of aminoglycoside to treat the
infections. Obviously, small concentration of aminoglycosides will reduce the toxicity as well as can
overcome the bacterial resistance; In India, resistance of common bacteria to widely used antibiotics is
prevalent. In a recent World Health Organisation pilot study, Multi Drug Resistance bacteria's (MDR)
was tracked for two years at large urban hospitals. MDR rates were high; at least 40 per cent for most
for all major classes of antibiotics.10
Status:
In recent years, few research groups are working in the area of aminoglycosides based medicinal
chemistry. In particular, Prof. Timor Baasov, Technion-Israel Institute of Technology- Israel; Prof.
Chi-Huey Wong, Scripps Research Institute; Prof. Cheng-Wei Tom Chang, Utah State University;
Prof. Stephen Hanessian, Université de Montréal, are actively contributing to this field. As far as
India is concerned, lot of scope is there in this interdisciplinary research filed as none of the groups
have specific contribution.
Experience and contributions:
I have three years post doctoral experience with Prof. Timor Baasov, Department of Chemistry,
Technion, Israel. My research experience includes design, synthesis and clinical applications of
aminoglycosides as potential drugs for human genetic diseases.4a,11,12 We have achieved a
breakthrough in finding a suitable aminoglycoside molecule for the treatment of genetic diseases that
has higher activity and much lower toxicity than current clinical trial drug, Gentamicin.11 Currently
this molecule is in drug development in Israel. Also this work has been very recently highlighted in
Chemistry World (RSC), http://www.rsc.org/chemistryworld/News/2011/February/22021101.asp. The
obtained results are submitted for publication.12
In addition to this, I have substantial research experience during my Ph.D program especially in
“Transition metals catalyzed organic transformations”. Most of the research experience revolves
around "Molybdenum (VI) Based Catalysts in Organic Transformations" which discusses about the
molybdenum(VI) dichloride dioxide (MoO2Cl2) and related adducts as catalysts for various organic
transformations.13-22
References:
1. Arya, D. P. (ed.) Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery, Wiley,
Hoboken, New Jersey (2007).
2. Hermann, T. Aminoglycoside antibiotics: Old drugs and new therapeutic approaches. Cell. Mol.
Life Sci. 2007, 64, 1841–1852.
3. Carter, A. P.; Clemons, W. M.; Brodersen, D. E.; Morgan-Warren, R. J.; Wimberly, B. T.;
Ramakrishnan, V. Functional insights from the structure of the 30S ribosomal subunit and its
interactions with antibiotics. Nature, 2000, 407, 340-348.
4. a) Pokrovskaya, V.; Nudelman, I.; Jeyakumar, K.; Baasov, T. Aminoglycosides: Redesign
strategies for improved antibiotics and compounds for treatment of human genetic diseases.
Methods in enzymology, 2010, 21, 437-462. b) Hainrichson, M., Nudelman, I., and Baasov, T.
5.
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Designer aminoglycosides: The race to develop improved antibiotics and compounds for the
treatment of human genetic diseases. Org. Biomol. Chem. 2008, 6, 227–239.
a) Tucker, J. L. Green Chemistry, a Pharmaceutical Perspective Org. Process Res. Dev. 2006, 10,
315-319. b) Patricia Van Arnum, Green Drug Delivery: Spray-dried solid amorphous dispersions
with a cellulosic exicpient. Pharmaceutical Technology, 34, 8, 43.
Han, H. K and Amidon, G.L. Targeted prodrug design to optimize drug delivery. AAPS Pharm
Sci. 2000, 2, E6.
a) Jill, A.-M and Richard T. liposomal formulation, structure, mechanism of action and preclinical
experience.
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Chemother.
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21–30. b)
http://en.wikipedia.org/wiki/Amphotericin_B.
Zarif, L. Drug Delivery by Lipid Cochleates, Methods in enzymology, 2005, 391, 314-329.
Santangelo, R., Paderu, P., Delmas, G., Chen, Z. W., Mannino, R., Zarif, L., and Perlin, D. S.
Efficacy of oral cochleate-amphotericin B in a mouse model of systemic candidiasis. Antimicrob.
Agents Chemother. 2000, 44, 2356–2360. 10. http://articles.timesofindia.indiatimes.com/2011-04-21/delhi/29458815_1_antibiotics-drug-resistancemulti-drug-resistance 11. Jeyakumar, K.; Glikin, D.; Belakhov, V.; Baasov, T.
"Repairing faulty genes by
aminoglycosides: Identification of new pharmacophore with enhanced suppression of diseasescausing nonsense mutations" Med. Chem. Commun., 2011, 2, 165-171 (Highlighted in
"Chemistry World" as HOT paper).
12. Jeyakumar, K.; Glikin, D.; Belakhov, V.; Baasov, T. "Fixing faulty genes by aminoglycosides:
Development of drug with superior activity of diseases-causing nonsense mutations" J. Med.
Chem., 2011, (communicated).
13. Jeyakumar, K.; Chakravarthy, R. D. and Chand, D. K. "Simple and efficient method for the
oxidation of sulfides to sulfones using hydrogen peroxide and a Mo(VI) based catalyst" Catal.
Commun. 2009, 10, 1948-1941.
14. Jeyakumar, K. and Chand, D. K. "Application of molybdenum(VI) dichloride dioxide (MoO2Cl2)
in organic transformations" J. Chem. Sci. 2009, 121, 111-123. [Highlighted in Cover Page].
15. Jeyakumar, K. and Chand, D. K. "Molybdenum(VI) dichloride dioxide catalyzed oxidation of βhydroxycarbonyls to α-bromo 1,3-dicarbonyls by N-bromosuccinimide" Synthesis, 2009, 306310.
16. Jeyakumar, K. and Chand, D. K. "Molybdenum(VI)/copper(II)- An efficient bimetallic catalyst
for aerobic oxidation of alcohols" Open Catal. J. 2008, 1, 6-11. [Invited article by the editor].
17. Jeyakumar, K. and Chand, D. K. "Molybdenum(VI) dichloride dioxide catalyzed synthesis of βketo esters by C–H insertion of ethyl diazoacetate into aldehydes" Synthesis, 2008, 1685-1687.
18. Jeyakumar, K. and Chand, D. K. "Ring opening reactions of epoxides catalyzed by
molybdenum(VI) dichloride dioxide" Synthesis, 2008, 807-819.
19. Jeyakumar, K. and Chand, D. K. "Copper perchlorate: Efficient acetylation catalyst under
solvent free conditions" J. Mol. Catal. A: Chem. 2006, 255, 275-282.
20. Jeyakumar, K. and Chand, D. K. "Selective oxidation of sulfides to sulfoxides and sulfones at
room temperature using H2O2 and a Mo(VI) salt as catalyst" Tetrahedron Lett., 2006, 47, 45734576. [Cited more than 50 times]
21. Jeyakumar, K. and Chand, D. K. "Aerobic oxidation of benzyl alcohols by Mo (VI) compounds"
Appl. Organometal. Chem. 2006, 20, 840-844.
22. Chand, D. K.; Manivannan, R.; Sahoo, H. S. and Jeyakumar, K. Self-assembly by ligandexchange reactions" Eur. J. Inorg. Chem. 2005, 3346–3352.