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Fulltext In silico identification of novel tuberculosis drug targets in mycobacterium tuberculosis P450 enzymes by interaction study with azole drugs

Suresh Kumar

Malaysian Journal of Medicine and Health Sciences, 2020;16(101):24-30.
MyJurnal

Introduction: Tuberculosis (TB) is one of the utmost serious infectious diseases worldwide. The emergence of multi- drug resistance demands the development of better or new putative drug targets for tuberculosis. Recent studies sug- gest Mycobacterium tuberculosis cytochrome P450 enzymes as promising drug targets and azole drugs as potential inhibitors. Methods: Various computational tools, like Expasy Protparam, Swiss model, RaptorX and Phyre2 were used to analyze 12 Mycobacterium tuberculosis P450 enzymes and determine their three-dimensional structure. The structural validation was done through a Ramachandran plot using RAMPAGE server. The docking of P450 enzymes with azole drugs was done with autodock ver 4.2.6. Results: Based on sub-cellular localization prediction using CEL- LO tool, P450 enzymes CYP123A1, CYP132A1, CYP135A1, CYP136A1, CYP140A1, and CYP143A1 were predicted to be in the cytoplasm. Through structure assessment by Ramachandran plot, the best homology modelled proteins were docked with azole drugs like clotrimazole, croconazole, econazole, fluconazole, itraconazole, itraconazole, ketaconazole and micronazole by using autodock. By docking method it is identified that ketaconazole drug has a high affinity towards most of the mycobacterium P450 enzymes followed by the itrconazole drug. CYP123A1 enzyme is preferable as a drug target due to high binding affinity towards ketoconazole followed by CYP135A1, CYP140A1 enzymes. Conclusion: This study would help in identifying putative novel drug targets in Mycobacterium tuberculosis, which can lead to promising candidates for the optimization and development of novel anti-mycobac- terial agents.
Fulltext Computational prediction of novel broad-spectrum drug targets against Vibrio cholerae by integrated genomics and proteomics approach

Suresh Kumar, Meera Ramanujam

Malaysian Journal of Medicine and Health Sciences, 2020;16(2):99-104.
MyJurnal

Introduction: Vibrio cholerae is a motile, Gram-negative curved rod belonging to the Vibrionaceae family. It is the causative agent of cholera. The acute diarrheal disease cholera causes about 120 000 casualties annually and has a significant effect on the health of young kids between the ages of 1 and 5. The main cause of death is due to resistance to antibiotics. As a result, new drug targets need to be identified immediately. The study’s goal is to identify Vibrio Cholerae’s putative drug target through an integrated approach to genomics and proteomics. Methods: Through this study, 2241 core protein sequence of Vibrio Cholerae were retrieved from the Panx tool. The sequence decreased to 173 druggable sequences by undergoing different phases of the process such as determining the non-homolo- gous sequence against human proteome by using the BlastP tool, identifying the essential genes by using the DEG database, and determining the sequence of virulent proteins by using Virulent prediction tool. Results: 11 potential drug targets were identified through molecular weight, and sub-cellular localization analysis. Conclusion: Through pan-genome analysis, we can able to find potential drug targets. This study also helps to identify the potential drug targets against Vibrio cholerae and to increase the efforts of drug and vaccine developments.
Fulltext Amoebic forms of Blastocystis spp. - evidence for a pathogenic role

Rajamanikam A, Govind SK

Parasit Vectors, 2013;6(1):295.
PMID: 24499467 DOI: 10.1186/1756-3305-6-295

Blastocystis spp. are one of the most prevalent parasites isolated from patients suffering from diarrhea, flatulence, constipation and vomiting. It's pathogenicity and pathophysiology remains controversial to date. Protease activity and amoebic forms have been reported previously in symptomatic isolates but there has been no conclusive evidence provided to correlate the protease activity and any specific life cycle stage of the parasite thus far.
Modified fields' stain: ideal to differentiate Dientamoeba fragilis and Blastocystis sp

Ragavan AD, Govind SK

Parasitol Res, 2015 Mar;114(3):1163-6.
PMID: 25614298 DOI: 10.1007/s00436-014-4296-8

Dientamoeba fragilis, a trichomonad parasite is usually found in the gastrointestinal tract of human, and it is known to be the cause for gastrointestinal disease. The parasite is globally distributed and mostly found in rural and urban areas. The parasite is found in humans and nonhuman primates such as the macaques, baboons, and gorillas. Often, the parasite is confused with another largely found organism in stools called Blastocystis sp. especially when seen directly under light microscopy on culture samples containing both parasites. Both sometimes are seen with two nuclei with sizes tending to be similar which complicates identification. Stools were collected fresh from nine previously diagnosed persons infected with D. fragilis who also were found to be positive for Blastocystis sp. Samples were then cultured in Loeffler's medium and were stained with Giemsa, iron hematoxylin, and modified Fields' (MF) stain, respectively. D. fragilis was differentiated from Blastocystis sp. when stained with MF stain by the presence of a thinner outer membrane with clearly demarcated nuclei in the center of the cell whilst Blastocystis sp. had a darker and thicker stained outer membrane with the presence of two nuclei. The staining contrast was more evident with modified Fields' stain when compared with the other two. The simplicity in preparing the stain as well as the speed of the staining procedure make MF stain an ideal alternate. The modified Fields' stain is faster and easier to prepare when compared to the other two stains. MF stain provides a better contrast differentiating the two organisms and therefore provides a more reliable diagnostic method to precisely identify one from the other especially when cultures show mixed infections.
Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors

Kia Y, Osman H, Suresh Kumar R, Basiri A, Murugaiyah V

Bioorg Med Chem Lett, 2014 Apr 1;24(7):1815-9.
PMID: 24594354 DOI: 10.1016/j.bmcl.2014.02.019

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
Silver nanoparticle functionalized CS-g-(CA-MA-PZA) carrier for sustainable anti-tuberculosis drug delivery

Amarnath Praphakar R, Jeyaraj M, Ahmed M, Suresh Kumar S, Rajan M

Int J Biol Macromol, 2018 Oct 15;118(Pt B):1627-1638.
PMID: 29981824 DOI: 10.1016/j.ijbiomac.2018.07.008

Recently, drug functionalized biodegradable polymers have been appreciated to be imperative to fabricate multi-drug delivery nanosystems for sustainable drug release. In this work, amphiphilic chitosan-grafted-(cetyl alcohol-maleic anhydride-pyrazinamide) (CS-g-(CA-MA-PZA)) was synthesized by multi-step reactions. The incorporation of rifampicin (RF) and entrapment of silver nanoparticles (Ag NPs) on CS-g-(CA-MA-PZA) polymer was carried out by dialysis technique. From the FT-IR experiment, the polymer modification, incorporation of drugs and the entrapment of Ag NPs on micelles were confirmed. The surface morphology of Ag NPs, polymeric system and drug loaded micelles was described by SEM, TEM and AFM techniques. In addition, the controlled release behaviour of CS-g-(CA-MA-PZA) micelles was studied by UV-Vis spectroscopy. In vitro cell viability, cell apoptosis and cellular uptake experiments shows that multi-drug delivery system could enhance the biocompatibility and higher the cytotoxicity effect on the cells. Since the prepared amphiphilic polymeric micelles exhibit spotty features and the system is a promising strategy for a novel candidate for immediate therapeutically effects for alveolar macrophages.
Misunderstanding of Leptospirosis

Teh SW, Mok PL, Subbiah SK

Acta Trop, 2019 09;197:105046.
PMID: 31158342 DOI: 10.1016/j.actatropica.2019.105046
Establishing a protocol for water sample processing for the detection of Blastocystis sp

Lee IL, Tan TC, Govind SK

Exp Parasitol, 2019 Mar;198:105-110.
PMID: 30695704 DOI: 10.1016/j.exppara.2019.01.007

This study was aimed at establishing a protocol for water sample processing for the detection of Blastocystis sp. using distilled water spiked with Blastocystis sp. cysts. The study established a protocol involving eight technical aspects, namely, storage temperature, storage duration, minimum water sample volume, optimum relative centrifugal force, centrifugation duration, minimum number of cyst for inoculation in Jones' medium and turn-around-time for the detection of vacuolar forms of Blastocystis sp. Results showed a minimum of 1.0 L water sample should be collected and processed on the same day. Otherwise, it should be stored at 4 °C and processed within 3 days. Water sample should be centrifuged at 1400×g for 10 min. For the isolation of Blastocystis sp. cysts, parasite pellet could be layered on top of Ficoll-Paque™ PLUS, centrifuged at 1400×g for 20 min and washed twice using 0.9% saline with centrifugation at 1400×g for 10 min. A minimum of 1 × 105 cysts could then be inoculated in Jones' medium supplement with 10% horse serum, incubated at 37 °C and examined for any presence of vacuolar forms of Blastocystis sp. after 3 days of inoculation. A protocol for water sample processing for the detection of Blastocystis sp. has successfully been established. The protocol was validated using 106 various water samples. This protocol will be very useful in determining the extent of Blastocystis sp. contamination in water sources in order to identify the seriousness of contamination.
Fulltext Development of loop-mediated isothermal amplification (LAMP) for the detection of speB gene in invasive Streptococcus pyogenes clinical isolates

Azi Simon Onyema, Leslie Than Thian Lung, Suresh Kumar, Rukman Awang Hamat

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):1-1.
MyJurnal

Introduction: Group A streptococcus (GAS) is responsible for high morbidity and mortality globally. Hence, the need to develop sensitive, reliable and cost- effective method of detection is crucial. In this study, we developed a visual detection method for the common virulence gene, streptococcal pyrogenic exotoxin B (speB) involved in invasive GAS diseases using loop-mediated isothermal amplification (LAMP) with fluorescent detection dye (calcein). Meth-ods: The LAMP reaction was optimized at 63°C for 35 minutes using five sets of primer designed with LAMP primer V5 software. When the dye was added prior to amplification, samples with speB DNA developed a characteristic green color after the reaction, but no color reactions were observed in samples with DNAs of non-GAS isolates. De-tection of speB by LAMP assay was done among 43 clinical isolates of blood, pus, wound, tissue and throat samples and ATCCs for controls. Our findings were further reconfirmed by subjecting the LAMP products to 0.5% gel electro-phoresis. Results: The detection limit of this LAMP assay for speB was 10-7 ng/μl of genomic DNA per reaction, which was 10,000-fold more sensitive than conventional PCR 10-3 ng/μl. All 100 % samples were positive for speB gene by LAMP, and 93% by conventional PCR method. Conclusion: LAMP assay could offer remarkably high sensitivity, specificity, repeatability, reliability, affordability, and visibility; it is appropriate for rapid detection of speB in Group A streptococci (GAS) as a point of care testing.
Fulltext Phenotypic variation in Blastocystis sp. ST3

Ragavan ND, Govind SK, Chye TT, Mahadeva S

Parasit Vectors, 2014;7:404.
PMID: 25174569 DOI: 10.1186/1756-3305-7-404

Blastocystis, is one of the most common human intestinal protozoan, which has many conflicting reports on its pathogenic role. Gut conditions which obviously varies in asymptomatic individuals, symptomatic and irritable bowel syndrome (IBS) patients in terms of gut flora, pH, osmotic pressure and water potentials could play an important role in its pathogenicity. The present study is the first study to investigate phenotypic characteristics of Blastocystis sp. ST3 isolated from asymptomatic, symptomatic and IBS isolates.
Fulltext A retrospective review on successful management of Penicillium marneffei infections in patients with advanced HIV in Hospital Sungai Buloh

Nor-Hayati S, Sahlawati M, Suresh-Kumar C, Lee KC

Med J Malaysia, 2012 Feb;67(1):66-70.
PMID: 22582551 MyJurnal

Penicillium marneffei is a dimorphic fungus which commonly causes a life threatening systemic fungal infection in an immunocompromised host. It has been recognized as an AIDS defining illness in Malaysia since the beginning of the HIV pandemic. The presence of various non specific clinical presentations, especially the characteristic umbilicated papular rashes with central necrosis which lead to significant ill health in immunocompromised patients should alarm clinicians to the possibility of Penicillium marneffei infection and prompt investigations accordingly. Simple investigations like blood culture and fungal staining of the skin scrapping can confirm the diagnosis in the majority of cases. Early treatment with appropriate systemic antifungal for a definite duration will significantly decrease the mortality rate from penicilliosis.
Fulltext Citrobacter koseri bacteraemia complicated by paraspinal abscess and spondylodiscitis--a case report

Shaharuddin NR, Leong CL, Chidambaram SK, Lee C

Med J Malaysia, 2012 Jun;67(3):337-9.
PMID: 23082432

Paraspinal abscess and spondylodiscitis due to Citrobacter koseri is a very rare condition. We report a remarkable case of Citrobacter koseri bacteraemia complicated by paraspinal abscess and spondylodiscitis in a patient who has successfully been treated in our hospital. Our patient demonstrates one of the common challenges in the practice of infectious disease medicine, wherein an innocuous presentation may and often underlie a serious infection. This case report elucidates to us that the diagnosis of a paraspinal abscess and spondylodiscitis requires a high index of suspicion in at risk patient presenting with compatible signs and symptoms.
Fulltext Blastocystis sp.: waterborne zoonotic organism, a possibility?

Lee LI, Chye TT, Karmacharya BM, Govind SK

Parasit Vectors, 2012;5:130.
PMID: 22741573 DOI: 10.1186/1756-3305-5-130

Blastocystis sp. is a common intestinal parasite found in faecal sample surveys. Several studies have implicated human-to-human, zoonotic and waterborne transmissions by Blastocystis sp. However, there has been no study providing evidence interlinking these three transmissions in a community. We have previously shown a high prevalence of Blastocystis sp. subtype 4 amongst village dwellers in Bahunipati, Nepal, and the present study extends the observation to assess if the same subtype of Blastocystis sp. occurs in animals they rear and rivers they frequent.
Therapeutic potential of Curcuma longa, the golden spice of India, in drug discovery for ophthalmic diseases

Agarwal R, Gupta SK, Srivastava S, Agarwal P, Agrawal SS

Expert Opin Drug Discov, 2009 Feb;4(2):147-58.
PMID: 23480513 DOI: 10.1517/13543770802668117

Curcuma longa is among the most commonly used spices in India and other Asian countries. The herb has also been used in Ayurveda and other traditional systems of medicine for the prevention and treatment of a variety of ailments. Curcuminoids are the major chemical constituents of C. longa that are of medicinal importance. Today, a large body of scientific evidence exists to indicate potential therapeutic benefits of C. longa. Several preclinical and clinical studies have investigated the pharmacological properties of C. longa and results indicate strong therapeutic potential for anti-inflammatory, antioxidant, antibacterial, anticancer and many other properties.
Factors that influence the shedding of Blastocystis cysts in an irritable bowel syndrome (IBS) patient--an evidence-based case study

Ragavan ND, Govind SK, Chye TT, Mahadeva S

Parasitol Res, 2015 Aug;114(8):2999-3005.
PMID: 25982571 DOI: 10.1007/s00436-015-4502-3

Blastocystis is one of the most common gut parasites found in the intestinal tract of humans and animals. We have previously reported the irregular shedding of Blastocystis cysts in stools from infected patients. In the present study, we assess the factors influencing shedding patterns from a Blastocystis ST3-infected IBS patient. The stools samples were voluntarily submitted for examination for a period of 30 days from Blastocystis ST3-infected IBS patient. A questionnaire on the factors that could influence the shedding pattern of the cysts was designed to assess the following information: (a) the frequency of frequenting the toilet in a day, (b) the timing of frequenting the toilet, (c) the stool forms, (d) the type of mood the patient was in when frequenting the toilet and (e) food intake. A total of 79 stool samples were collected for 30 days. The highest number of cysts recorded when the patient visited the toilet three times a day was 22.2 × 10(6) cysts/g. Frequenting the toilet between 6 a.m. to 11.59 a.m. showed the highest number of cysts, i.e. 21.7 × 10(6) cysts/g. Semi-solid forms showed the highest cyst count, i.e. 2.00 × 10(6) cysts/g. Irregular shedding of cysts was seen in 10 out of 30 days where the widest range recorded on day 17 was between 0 to 1.2 × 10(6) cysts/g. The average daily cyst count on days of emotional fluctuations was from 0 to 5.13 × 10(6) cysts/g. In conclusion, the study confirms that there are factors influencing shedding patterns of Blastocystis, and these have important implications when it comes to diagnosis and transmission of the parasite.
Irregular shedding of Blastocystis hominis

Vennila GD, Suresh Kumar G, Khairul Anuar A, Rajah S, Saminathan R, Sivanandan S, et al.

Parasitol Res, 1999 Feb;85(2):162-4.
PMID: 9934969

The shedding pattern of the protozoan parasite, Blastocystis hominis, is investigated in man and in experimental animal infections. The shedding pattern of the vacuolar and cystic forms of Blastocystis hominis in infected individuals have been shown in the present study to be irregular. The study shows that there is marked fluctuation in the shedding of the parasite from day to day, varying from as high as 17 to 0 per x40 microscopic field. The cystic stages when estimated in 8 Blastocystis-infected individuals ranged from as high as 7.4x10(5) cysts per gram of stool to 0. The shedding of cystic and vacuolar forms observed over a period of 20 days in experimentally-infected Wistar rats were not only shown to be irregular but the amount varied from host to host. The study has important diagnostic implications in that the stool samples must be collected more than once from patients showing clinical signs and symptoms to eliminate the cause of it to Blastocystis. The study also shows that there are asymptomatic individuals who pass a large amount of cysts as such individuals should be treated to prevent transmission to others.
Fulltext Complete recovery of filler-induced visual loss following subcutaneous hyaluronidase injection

Sharudin SN, Ismail MF, Mohamad NF, Vasudevan SK

Neuroophthalmology, 2019 Apr;43(2):102-106.
PMID: 31312234 DOI: 10.1080/01658107.2018.1482358

The rise in popularity of hyaluronic acid (HA) dermal filler injection has caused an exceptional increase in the number of cases of reported irreversible blindness. Here, we reported a case of ischemic optic neuropathy and ophthalmoplegia following subcutaneous HA filler injection with complete visual recovery. A 31-year-old Chinese woman presented with sudden onset of right monocular visual impairment associated with diplopia. Patient had received a hyaluronic acid-containing ﬁller injection for nasal dorsum augmentation twelve hours prior to presentation. Visual acuity of the right eye was counting finger. A right relative afferent pupillary defect was demonstrated with ophthalmoplegia. Humphrey visual field test disclosed a right inferior altitudinal field defect with impairment of colour vision. Computed tomography of the orbit revealed mild enlargement of the right medial and inferior recti muscles. Our patient showed a tremendous improvement of vision after a subcutaneous hyaluronidase injection with complete visual recovery within 2 weeks.
Risk factors of carbapenem-resistant Enterobacteriaceae infection and colonisation: a Malaysian tertiary care hospital based case-control study

Chuah CH, Gani Y, Sim B, Chidambaram SK

J R Coll Physicians Edinb, 2021 03;51(1):24-30.
PMID: 33877130 DOI: 10.4997/JRCPE.2021.107

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infection has become a major challenge to clinicians. The aim of this study is to identify the risk factors of acquiring CRE to guide more targeted screening for hospital admissions.
METHODS: This is a retrospective case-control study (ratio 1:1) where a patient with CRE infection or colonisation was matched with a control. The control was an individual who tested negative for CRE but was a close contact of a patient testing positive and was admitted at the same time and place. Univariate and multivariate statistical analyses were done.
RESULTS: The study included 154 patients. The majority of the CRE was Klebsiella species (83%). From univariate analysis, the significant risk factors were having a history of indwelling devices (OR: 2.791; 95% CI: 1.384-5.629), concomitant other MDRO (OR: 2.556; 95% CI: 1.144-5.707) and hospitalisation for more than three weeks (OR: 2.331; 95% CI: 1.163-4.673). Multivariate analysis showed that being unable to ambulate on admission (adjusted OR: 2.345; 95% CI: 1.170-4.699) and antibiotic exposure (adjusted OR: 3.515; 95% CI: 1.377-8.972) were independent predictors. The in-hospital mortality rate of CRE infection was high (64.5%). CRE acquisition resulted in prolonged hospitalisation (median=35 days; P<0.001).
CONCLUSION: CRE infection results in high morbidity and mortality. On top of the common risk factors, patients with mobility restriction, prior antibiotic exposures and hospitalisation for more than three weeks should be prioritised in the screening strategy to control the spread of CRE.
Fulltext Letter from Malaysia

Sirol Aflah SS, Mohd Thabit AA, Chidambaram SK

Respirology, 2021 06;26(6):624-626.
PMID: 33843115 DOI: 10.1111/resp.14057
Fulltext Editorial: Neurodegenerative eye diseases: Molecular mechanisms of neurogenesis and therapeutic perspectives

Mok PL, Catherine BM, Subbiah SK, Higuchi A

Front Cell Neurosci, 2022;16:1060266.
PMID: 36385951 DOI: 10.3389/fncel.2022.1060266

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