Ocular Anti Infective & Inflammation | Singapore National Eye Centre

Overview

The evolution of antimicrobial resistant pathogens is regarded as clinical “super challenges” of the 21st Century. In ophthalmology, infectious keratitis remains one of the most important causes of corneal blindness globally, and is especially prevalent in Asia, while endophthalmitis remains the most devastating complication following elective ophthalmic surgery at a global level.

Fungal infections, and the development of antimicrobial resistant bacterial infections remain major global challenges affecting populations today. At the same time, there has been a marked decrease in discovery and development of new antibiotics owing to unfavourable economic return and challenges in gaining approval. In addition, advances in the medical materials have brought about the use of metals and plastics for restoring or replacing the damaged body parts. However, harmful bacteria and fungus adhered to surgical tools, contact lenses, lens cases, medical implants and fixation devices pose significant threat to the patients. If unchecked, the colonised bacteria may increase hospital stay duration, costs as well as affect the quality of life leading to increased number of deaths.

An estimated 1.4 million people suffer from infectious complications acquired in the hospitals every year. With the world population ageing rapidly, there will be a large number of elderly patients who are immunocompromised and more susceptible to infections, many times stemming from surgical sites, burns, chronic wounds, catheter insertion sites or contact lens infections, among others.

The ultimate aim of our group is to collaborate with peers around the world to understand the evolution of antimicrobial resistance among the infectious keratitis patients as well as to develop strategies that might accelerate the rational design of antimicrobials and antimicrobial formulations.

Projects

Asia Cornea Society for Infectious Keratitis Study (ACSIKS): ACSIKS is a Pan-Asian study commissioned by the Asia Cornea Society to determine the demographics, risk factors, microbiology, clinical outcomes and antimicrobial resistance pattern among infectious keratitis patients throughout Asia. The largest study of its kind, involving over 6,500 patients, the study covers 13 different centres involving 8 countries in Asia: China, India, Japan, Philippines, Singapore, South Korea, Taiwan and Thailand. The specific goals of the program are:
- Standardisation of protocol for the study of infectious keratitis across various centres.
- Determination of the demographic profile and identification of the key risk factors associated with infectious keratitis in Asian countries
- To depict the current medical and surgical practice patterns for infectious keratitis
- To document the range of microorganisms causing infectious keratitis and the patterns of antibiotic resistance for bacterial isolates and
- To establish Central Repositories for the bacterial and fungal organisms isolated, for subsequent studies on microbial resistance and to aid future development of therapeutic agents
  
  Bacterial and fungal isolates from ACSIKS are currently housed in SERI’s ACSIKS Repository, and microbiological studies are currently underway to further identify organisms and antimicrobial resistance patterns, whilst serving as an important resource for evaluating therapeutic responses to new antimicrobial therapies.
Collaborative Ocular Tuberculosis Study (COTS): Ocular infections encompasses a wide array of potential pathogens with heterogeneous presentations. In an increasingly global ophthalmic world with new emerging infections, this area of ophthalmology demands the attention of all clinicians and scientists, any one of whom may encounter situations with puzzling presentations related to infectious causes. While the clinicians struggle to establish universally acceptable guidelines for treatment of ocular infectious disease, the scientists are challenged with the newer antimicrobials and increasing resistance to currently available molecules. Through the consortium of Collaborative Ocular Tuberculosis Study (COTS) (www.oculartb.net) and infectious uveitis network (www.infectiousuveitis.org) established by Assoc Prof Agrawal and team, the clinicians are trying to establish evidence-based algorithm for management of intraocular infectious diseases related to ocular tuberculosis, syphilis, viral uveitis, fungal endophthalmitis, toxoplasmosis. The ocular infections team will look into molecular mechanisms of ocular infectious disease and newer treatment options for management of recalcitrant ocular infectious disease.
Combatting Antimicrobial Resistance by Cell-Selective, Pore-Forming Peptides & Polymers: One of the strategies to combat antimicrobial resistance is through the development of membrane-targeting antimicrobial peptides & polymers. We use both de novo and rational design principles to synthesise antimicrobial peptides and polymers. The polymers or the peptides target the microbial cells with greater affinity than mammalian cells, thus enhancing their therapeutic potential. The designed polymers promote cell migration in the presence of wound inhibitory factors thus expanding their utility as antimicrobials as well as averting exaggerated inflammation.
Enhancing the Drug permeability by Combination Therapy: Owing to their relatively larger size, antimicrobial peptides must interact with outer membrane components of the Gram-negative bacteria prior to the disruption of cytoplasmic membrane. We determined that by disrupting the supramolecular organisation of lipopolysaccharides (the major OM component), branched peptides enhanced the permeability of various classes of antibiotics. The use of peptides that have strong affinity for bacterial outer membrane/cell wall components which are absent in mammalian cells would overcome the drawbacks associated with antimicrobial peptides.
Nature-inspired Antimicrobial Nanocoatings for Infection Control: Ultrafine nanofibres with broad spectrum antimicrobial properties are indispensable in the areas of tissue engineering and regenerative medicine, advanced wound dressings, personal protective equipment, sustained drug delivery and intelligent implants. To achieve this goal, we have developed a number of strategies that confer broad spectrum antimicrobial properties of medical devices, tissue engineering scaffolds, advanced wound dressings and sustained drug delivery.

Core Competencies

The research and development capability of The Ocular Anti Infective & Inflammation Research Group has been achieved through a series of outstanding collaborations with local and overseas universities and institutes. Our important participating universities or institutes include Singapore National Eye Center, Bio-Informatics Institute, Institute of Materials Research & Engineering, Tan Tock Seng Hospital, Burn Centre@Singapore General Hospital, Lee Kong Chian (LKC) School of Medicine (at Nanyang Technological University), Departments of Pharmacy and Mechanical Engineering (at National University of Singapore). In addition, we collaborate with overseas collaborators on various aspects of antimicrobials peptide design. Our key collaborators include the University of Liverpool, the University of Nottingham and the Tianjin University. The following are our core competencies:

Screening of antimicrobials against wide range of resistance as well as susceptible microbes
Determination of the mechanism of action of membrane-targeting antimicrobials
Safety and efficacy of antimicrobials in mice and rabbit models of bacterial and fungal keratitis
Laboratory and pilot scale preparation of nanofibres
Big data analytics and AI model using the global consortium and network related to ocular infections

Publications

Khor WB, Prajna VN, Garg P, Mehta JS, Xie L, Liu Z, Padilla MDB, Joo CK, Inoue Y, Goseyarakwong P, Hu FR, Nishida K, Kinoshita S, Puangsricharern V, Tan AL, Beuerman R, Young A, Sharma N, Haaland B, Mah FS, Tu EY, Stapleton FJ, Abbott RL, Tan DT; ACSIKS Group. The Asia Cornea Society Infectious Keratitis Study: A Prospective Multicenter Study of Infectious Keratitis in Asia. Am J Ophthalmol. 2018;195:161-170.
Agrawal R, Testi I, Bodaghi B, Barisani-Asenbauer T, McCluskey P, Agarwal A, Kempen JH, Gupta A, Smith JR, de Smet MD, Yuen YS, Mahajan S, Kon OM, Nguyen QD, Pavesio C, Gupta V; for COTS CON group. Collaborative Ocular Tuberculosis Study (COTS) Consensus Guidelines on the Management of Tubercular Uveitis - Report 2: Guidelines for Initiating Anti-Tubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis and Retinal Vasculitis. Ophthalmol. 2020;S0161-6420: 30598-4.
Agrawal R, Testi I, Mahajan S, Yuen YS, Agarwal A, Kon OM, Barisani-Asenbauer T, Kempen JH, Gupta A, Jabs DA, Smith JR, Nguyen QD, Pavesio C, Gupta V; Collaborative Ocular Tuberculosis Study Consensus Group. Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis. Ophthalmology. 2020;S0161-6420: 30013-0.
Agrawal R, Gunasekeran DV, Raje D, Agarwal A, Nguyen QD, Kon OM, Pavesio C, Gupta V; Collaborative Ocular Tuberculosis Study Group. Global Variations and Challenges With Tubercular Uveitis in the Collaborative Ocular Tuberculosis Study. Invest Ophthalmol Vis Sci. 2018;59:4162-4171.
Agrawal R, Gunasekeran DV, Grant R, Agarwal A, Kon OM, Nguyen QD, Pavesio C, Gupta V; Collaborative Ocular Tuberculosis Study (COTS)–1 Study Group. Clinical Features and Outcomes of Patients With Tubercular Uveitis Treated With Antitubercular Therapy in the Collaborative Ocular Tuberculosis Study (COTS)-1. JAMA Ophthalmol. 2017;135:1318-1327.
Saraswathi P, Beuerman RW. Corneal Biofilms: From Planktonic to Microcolony Formation in an Experimental Keratitis Infection with Pseudomonas aeruginosa. Ocul Surf. 2015;13:331-45.
Venkatesh M; Barathi VA; Goh ETL; Angaara R; Fazil MHUT; Ng AJY; Aung TT; Liu S; Yang L; Loh XJ; Beuerman RW; Verma NK; Lakshminarayanan R. Antimicrobial Activity and cell selectivity of synthetic and biosynthetic cationic polymer. Antimicrob. Agents Chemother. 2017;61. pii: e00469-17.
Venkatesh M, Xi Q, Goh ETL, Toh TYJ, Barathi VA, Fazil MHUT, Varadharajan J, Ting DSJ, Beuerman RW, Chan LW, Agrawal R, Barkham TMS, Verma NK, Lakshminarayanan R. Rational substitution of -lysine for -lysine enhances the cell and the membrane selectivity of pore-forming melittin. J Med Chem. 2020;63:3522-3537.
Aung TT, Chor WHJ, Lynn MN, Chan ASY, Tan DTH, Beuerman RW. Rabbit Fungal Keratitis Model of Fusarium solani Tested Against Three Commercially Available Antifungal Drugs. Eye Contact Lens. 2020 (In Press)
Dhand C; Venkatesh M; Barathi VA; Harini S; Bairagi S; Goh ETL; Nandhakumar M; Low KZW; Fazil MHUT; Verma NK; Loh XJ; Liu SP; Beuerman RW; Ramakrishna S; Lakshminarayanan R. Bio-inspired crosslinking and matrix-drug interactions for advanced wound dressings with long-term antimicrobial activity. Biomaterials. 2017;138:153-168.
Venkatesh M, Choong ACW, Dhand C, Lim FP, Tun AT, Sriram H, Dwivedi N, Periayah MH, Sridhar S, Fazil MHUT, Goh ETL, Orive G, Beuerman RW, Barkham TMS, Liang ZX, Barathi VA, Ramakrishna S, Chong SJ, Verma NK, Lakshminarayanan R. Multifunctional Antimicrobial Nanofiber Dressings Containing ε-Polylysine for the Eradication of Bacterial Bioburden and Promotion of Wound Healing in Critically Colonized Wounds. ACS Appl Mater Interfaces. 2020;12: 15989-16005.
Dhand C, Ong CY, Dwivedi N, Venkatesh M, Goh ETL, Chan LW, Beuerman RW, Foo LL, Loh XJ, Lakshminarayanan R. Mussel-Inspired Durable Antimicrobial Contact Lenses: The Role of Covalent and Non-covalent Attachment of Antimicrobials. ACS Biomat Sci Eng. 2020;5: 3162-3173.
Balne PK; Harini S; Dhand C; Dwivedi N; Chalasani MS; Verma NK; Barathi VA; Beuerman RW; Agrawarl R and Lakshminarayanan R. Surface characteristics and antimicrobial properties of modified catheter surfaces by pyrogallol and metal ions. Mater. Sci. Eng. C Mater. Biol. 2018;90: 673-684.
Tan XW; Goh TW; Saraswathi P; Nyein CL; Setiawan M; Riau A; Lakshminarayanan R; Liu SP; Tan D; Beuerman RW; Mehta JS. Effectiveness of antimicrobial peptide immobilization for preventing perioperative cornea implant-associated bacterial infection. Antimicrob. Agents Chemother. 2014; 58: 5229-5383.