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  1. Bavanandan S, Morad Z, Ismail O, Chandran A, Thayaparan T, Singaraveloo M
    Med J Malaysia, 2005 Jun;60(2):158-62.
    PMID: 16114156 MyJurnal
    This study was conducted to determine the tolerability and efficacy of valsartan (DIOVAN) compared to perindopril (COVERSYL) in Malaysian patients with mild to moderate hypertension. Two hundred and fifty adult Malaysian patients with a mean sitting diastolic blood pressure of more than 95 mmHg and less than 115 mmHg after a 14 day washout period were randomized to receive either valsartan 80 mg once daily (n=125) or perindopril 4 mg daily (n=125) for eight weeks. The primary end point for efficacy was the change in mean sitting systolic and diastolic blood pressure (SiSBP and SiDBP). The primary criteria for evaluation of tolerability was the incidence of adverse events. There were no significant differences between the two groups with respect to sex, age, weight, baseline sitting and standing systolic and diastolic blood pressure. At 0, 4 and 8 weeks the mean SiDBP in the valsartan group were 101.4, 92.8 and 91.0 mmHg respectively. The corresponding BP for the perindopril treated group was 102.6, 93.8 and 93.2 mmHg. (95% CI -1.39 to +3.27). There were no significant differences in the mean BP measurements between the valsartan and perindopril group at 0, 4 and 8 weeks. In each group there were significant differences between the BP at 4 and 8 weeks compared to baseline. A similar pattern was seen with SiSBP. At 4 weeks 28.7% of the valsartan and 25% of the perindopril group had their BP normalized (SiDBP <90 mmHg) The percentages of patients who responded (SiDBP reduction >10 mmHg but SiDBP >90 mmHg) were 21.3 in the valsartan group and 20.8 in the perindopril group. At 8 weeks, 31.1% of the valsartan group and 30.8% of the perindopril group had their BP normalized. The response rate was 27% and 22.5% for valsartan and perindopril respectively. The major adverse event was cough which occurred in 18 patients (14.4%) in the perindopril and 1 (0.8%) in the valsartan group at 4 weeks. At 8 weeks the figures were 24 (19.2%) and 2 (1.6%) respectively. The results indicate that Valsartan is safe and efficacious in the treatment of mild to moderate hypertension. It is equally efficacious to Perindopril and not associated with any major adverse event. It has a better tolerability profile with respect to dry cough.
  2. Chandran A, Selva Kumar S, Hairi NN, Low WY, Mustapha FI
    Front Public Health, 2021;9:698741.
    PMID: 34295873 DOI: 10.3389/fpubh.2021.698741
    In 2012, the World Health Organization (WHO) set a comprehensive set of nine global voluntary targets, including the landmark "25 by 25" mortality reduction target, and 25 indicators. WHO has also highlighted the importance of Non-Communicable Disease (NCD) surveillance as a key action by Member States in addressing NCDs. This study aimed to examine the current national NCD surveillance tools, activities and performance in Malaysia based on the WHO Global Monitoring Framework for NCDs and to highlight gaps and priorities moving forward. A desk review was conducted from August to October in 2020, to examine the current national NCD surveillance activities in Malaysia from multiple sources. Policy and program documents relating to NCD surveillance in Malaysia from 2010 to 2020 were identified and analyzed. The findings of this review are presented according to the three major themes of the Global Monitoring Framework: monitoring of exposure/risk factor, monitoring of outcomes and health system capacity/response. Currently, there is a robust monitoring system for NCD Surveillance in Malaysia for indicators that are monitored by the WHO NCD Global Monitoring Framework, particularly for outcome and exposure monitoring. However, Malaysia still lacks data for the surveillance of the health system indicators of the framework. Although Malaysia has an NCD surveillance in place that is adequate for the WHO NCD Global Monitoring Framework, there are areas that require strengthening. The country must also look beyond these set of indicators in view of the increasing burden and impact of the COVID-19 pandemic. This includes incorporating mental health indicators and leveraging on alternate sources of data relating to behaviors.
  3. Eng CW, Lim SC, Ngongo C, Sham ZH, Kataria I, Chandran A, et al.
    BMC Public Health, 2022 Jan 28;22(1):192.
    PMID: 35090429 DOI: 10.1186/s12889-022-12598-y
    BACKGROUND: Malaysia has the highest rate of overweight and obesity among Asian countries. Obesity is increasing particularly among low-income populations. This study aimed to assess dietary practices among low-income adults in urban communities, including gender and ethnic variation, to inform the development of locally tailored, evidence-based interventions for health promotion.

    METHODS: This cross-sectional study was conducted from August to December 2020. Stratified sampling was employed to recruit 2983 low-income adults from households in the bottom 40% of the economic spectrum (B40) at six public, low-cost housing flats in the Federal Territory of Kuala Lumpur, Malaysia. Face-to-face interviews were conducted using a structured questionnaire to understand dietary practices, perceptions of healthy food availability and affordability, and factors affecting food purchasing decisions.

    RESULTS: A staggering 89.5% of B40 adults were found to not consume adequate daily amounts of fruits and vegetables. In addition, 68.1% reported consuming sugar-sweetened beverages at least once per week, including commercially packed ready-to-drink beverages, sugar-added self-prepared drinks, and premixed drinks. Intake was statistically significantly higher among men (71.7%), Malays (70.3%), and Indians (69.9%). Bread and other commercially baked goods were the most common processed foods, and 52.9% of respondents consumed it at least once per week. Majorities reported that healthy foods were moderately available and priced. The top three reported factors affecting food purchase choices were price (79.4%), availability (75%), and taste (73%).

    CONCLUSIONS: Adults in low-cost housing communities have unhealthy dietary patterns with low intake of fruits and vegetables and high intake of ultra-processed foods and calorie-dense local foods, with variations across gender and ethnicity. The study highlighted the need for educating low-income families on diet-disease relationships and possibilities for inexpensive, healthy eating that rely on minimally processed fresh foods. Policymakers engaging the food industry are advised to consider how to increase the affordability and availability of healthy foods in low-income communities in urban areas.

  4. Chee KH, Choo GH, Jamaluddin ANB, Mahendran K, Greenlaw N, Chandran A
    Med J Malaysia, 2017 10;72(5):282-285.
    PMID: 29197883 MyJurnal
    INTRODUCTION: The on-going, international, prospective, observational, longitudinal CLARIFY registry is investigating the demographics, clinical profiles, management and outcomes of patients with stable coronary artery disease (CAD). This paper assesses baseline characteristics, treatment, and clinical outcomes at two years' follow-up of Malaysian/Bruneian patients compared with the overall registry population.

    METHOD: Between November 2009 and July 2010, outpatients from 45 countries who met the criteria for stable CAD were recruited into the registry. Baseline characteristics were documented at enrolment, and patients were reassessed during their annual visits over a five-year follow-up period. Key outcomes measured were sudden death and cardiovascular (CV) death, non-CV death and CV morbidity.

    RESULTS: At baseline, 33,283 patients were available for analysis within the registry; 380 and 27 were Malaysians and Bruneians, respectively. The mean ages of Malaysian/Bruneian patients and the rest of the world (RoW) were 57.83 ±9.98 years and 64.23 ± 10.46 years, respectively (p<0.001). The median body mass index values were 26.6 (24.4-29.6) kg/m2 and 27.3 (24.8-30.3) kg/m2, respectively (p=0.014). Malaysian/Bruneian patients had lower rates of myocardial infarction (54.55% versus 59.76%, p=0.033) and higher rates of diabetes (43.24% versus 28.99%, p<0.001) and dyslipidaemia (90.42% versus 74.66%, p<0.001) compared with the RoW. Measured clinical outcomes in Malaysian and Bruneian patients at 2-years follow-up were low and generally comparable to the RoW.

    CONCLUSION: Malaysian/Bruneian patients with stable CAD tend to be younger with poorer diabetic control compared with the RoW. However, they had similar outcomes as the main registry following two years of treatment.

  5. Kumar SS, Hartner AM, Chandran A, Gaythorpe KAM, Li X
    BMC Public Health, 2023 Nov 28;23(1):2351.
    PMID: 38017415 DOI: 10.1186/s12889-023-17082-9
    BACKGROUND: Malaysia introduced the two dose measles-mumps-rubella (MMR) vaccine in 2004 as part of its measles elimination strategy. However, despite high historical coverage of MCV1 and MCV2, Malaysia continues to report high measles incidence. This study suggests a novel indicator for investigating population immunity against measles in the Malaysian population.

    METHODS: We define effective vaccine coverage (EVC) of measles as the proportion of a population vaccinated with measles-containing vaccine (MCV) and effectively protected against measles infection. A quantitative evaluation of EVC throughout the life course of Malaysian birth cohorts was conducted accounting for both vaccine efficacy (VE) and between-dose correlation (BdC). Measles vaccination coverage was sourced from WHO-UNICEF estimates of Malaysia's routine immunisation coverage and supplementary immunisation activities (SIAs). United Nations World population estimates and projections (UNWPP) provided birth cohort sizes stratified by age and year. A step wise joint Bernoulli distribution was used to proportionate the Malaysian population born between 1982, the first year of Malaysia's measles vaccination programme, and 2021, into individuals who received zero dose, one dose and multiple doses of MCV. VE estimates by age and doses received are then adopted to derive EVC. A sensitivity analysis was conducted using 1000 random combinations of BdC and VE parameters.

    RESULTS: This study suggests that no birth cohort in the Malaysian population has achieved > 95% population immunity (EVC) conferred through measles vaccination since the measles immunisation programme began in Malaysia.

    CONCLUSION: The persistence of measles in Malaysia is due to pockets of insufficient vaccination coverage against measles in the population. Monitoring BdC through immunisation surveillance systems may allow for the identification of susceptible subpopulations (primarily zero-dose MCV individuals) and increase the coverage of individuals who are vaccinated with multiple doses of MCV. This study provides a tool for assessment of national-level population immunity of measles conferred through vaccination and does not consider subnational heterogeneity or vaccine waning. This tool can be readily applied to other regions and vaccine-preventable diseases.

  6. McKenzie BL, Mustapha FI, Battumur BE, Batsaikhan E, Chandran A, Michael V, et al.
    Public Health Nutr, 2024 Feb 12;27(1):e89.
    PMID: 38343162 DOI: 10.1017/S1368980023002781
    OBJECTIVE: To understand the extent to which national salt reduction strategies in Malaysia and Mongolia were implemented and achieving their intended outcomes.

    DESIGN: Multiple methods process evaluations conducted at the mid-point of strategy implementation, guided by theoretical frameworks.

    SETTING: Malaysia (2018-2019) and Mongolia (2020-2021).

    PARTICIPANTS: Desk-based reviews of related documents, interviews with key stakeholders (n 12 Malaysia, n 10 Mongolia), focus group discussions with health professionals in Malaysia (n 43) and health provider surveys in Mongolia (n 12).

    RESULTS: Both countries generated high-quality local evidence about salt intake and levels in foods and culturally specific education resources. In Malaysia, education and reformulation activities were delivered with moderate dose (quantity) but reach among the population was low. Within 5 years, Mongolia implemented education among schools, health professionals and food producers on salt reduction with high reach, but with moderate dose (quantity) and reach among the general population. Both countries faced challenges in implementing legislative interventions (mandatory salt labelling and salt limits in packaged foods) and both could improve the scaling up of their reformulation and education activities.

    CONCLUSIONS: In the first half of Malaysia's and Mongolia's strategies, both countries generated necessary evidence and education materials, mobilised health professionals to deliver salt reduction education and achieved small-scale reformulation in foods. Both subsequently should focus on implementing regulatory policies and achieving population-wide reach and impact. Process evaluations of existing salt reduction strategies can help strengthen intervention delivery, aiding achievement of WHO's 30 % reduction in salt intake by 2025 target.

  7. Lim SC, Kataria I, Ngongo C, Usek VS, Kudtarkar SR, Chandran A, et al.
    Glob Health Promot, 2022 May 16;29(4):17579759221091197.
    PMID: 35578553 DOI: 10.1177/17579759221091197
    BACKGROUND: The COVID-19 pandemic led Malaysia to introduce movement control orders (MCOs). While MCOs were intended to slow the spread of COVID-19, the effects of such measures on the noncommunicable disease (NCD) risk factors have not been fully explored. This exploratory study aimed to understand the effect of the MCO on the eating habits and physical activity levels of the urban poor in Malaysia as well as potential health promotion interventions during the COVID-19 pandemic.

    METHODS: This rapid assessment used a mixed-method approach in three low-cost public flats in Kuala Lumpur targeting the B40, which is the bottom 40% of the economic spectrum. A total of 95 community members participated in a quantitative phone survey, while 21 respondents participated in a qualitative phone survey, including 12 community members and nine community health volunteers (CHVs).

    RESULTS: The movement restriction imposed during the MCO significantly reduced the frequency and duration of respondents' physical activity. At the same time, respondents reported significantly increased consumption of home-cooked meals. More than half of respondents reduced their consumption of packaged snack foods (53.7%), street desserts (54.7%), fast food (50.5%), soft drinks (50.5%), and 3-in-1 or instant drinks (50.5%) due to limited access during the MCO. B40 communities were receptive to potential interventions to encourage healthier eating and physical activity leveraging digital approaches under the 'new normal'. Reported concerns included internet accessibility and affordability, functionality, and digital literacy.

    CONCLUSION: The COVID-19 pandemic requires innovation to address diseases and risk factors at the community level. While movement restrictions reduced physical activity, they created opportunities for low-income individuals to have greater control over their diet, enabling them to adopt healthier eating habits. Lifestyle changes experienced by vulnerable populations provide an opportunity for creative and technology-enabled interventions to promote healthy eating and exercise.

  8. Kataria I, Ngongo C, Lim SC, Kocher E, Kowal P, Chandran A, et al.
    PMID: 33033807 DOI: 10.1186/s43058-020-00080-y
    Background: Noncommunicable disease burden is rising in Malaysia, accounting for 72% of all deaths. Urbanization and globalization have contributed to changing patterns of diet and physical activity, creating an obesogenic environment that increases noncommunicable disease risk, especially in low-income populations. Community-based and technological interventions can play an important role in addressing structural determinants that influence noncommunicable disease burden. The Better Health Programme Malaysia aims to co-create and develop a community-based digital intervention for low-income populations to enable community stakeholders to address obesogenic environments and improve people's knowledge, attitudes, and practices related to noncommunicable disease risk.

    Methods: This quasi-experimental study will assess community member and community health volunteer knowledge, attitudes, and practices on noncommunicable disease prevention, risk factors, and health-seeking behavior in three geographical areas of Kuala Lumpur, each representing a different ethnicity (Malay, Indian, and Chinese). Assessment will take place before and after a 9-month intervention period, comparing intervention areas with matched control geographies. We plan to engage 2880 community members and 45 community health volunteers across the six geographic areas. A digital health needs assessment will inform modification of digital health tools to support project aims. Intervention co-creation will use a discrete choice experiment to identify community preferences among evidence-based intervention options, building from data collected on community knowledge, attitudes, and practices. Community health volunteers will work with local businesses and other stakeholders to effect change in obesogenic environments and NCD risk. The study has been approved by the Malaysian Ministry of Health Medical Research Ethical Committee.

    Discussion: The Better Health Programme Malaysia anticipates a bottom-up approach that relies on community health volunteers collaborating with local businesses to implement activities that address obesogenic environments and improve community knowledge, attitudes, and practices related to NCD risk. The planned co-creation process will determine which interventions will be most locally relevant, feasible, and needed. The effort aims to empower community members and community health volunteers to drive change that improves their own health and wellbeing. The learnings can be useful nationally and sub-nationally in Malaysia, as well as across similar settings that are working with community stakeholders to reduce noncommunicable disease risk.

    Trial registration: National Medical Research Register, Malaysia; NMRR-20-1004-54787 (IIR); July 7, 2020.

  9. Kocher E, Wood D, Lim SC, Jackson-Morris A, Kataria I, Ngongo C, et al.
    Health Promot Int, 2022 Dec 01;37(6).
    PMID: 36367424 DOI: 10.1093/heapro/daac156
    Non-communicable diseases and associated risk factors, such as obesity, are prevalent and increasing in Malaysia. To address this burden and the heightened vulnerability of low-income communities to these risk factors, the Better Health Programme Malaysia conducted a partial-profile discrete choice experiment (DCE) to inform the design of a community-based obesity-prevention programme. The DCE survey was conducted with community members (n = 1453) from three publicly supported low-cost, high-rise flat complexes in urban Kuala Lumpur. In the survey, community members were asked to choose between different sets of potential evidence-based interventions for obesity prevention. Their responses to these choice tasks were analysed to quantify preferences for these different health interventions using a random utility maximization model. Based on these results, we determined participants' relative prioritization of the different options. The most preferred interventions were those that reduced the price of fruit and vegetables; altered cooking practices at restaurants and food vendors to reduce salt, sugar and oil; and offered reward incentives for completing online educational activities. Community members did not prioritize several evidence-based interventions, including changes to product placement or product labelling, suggesting that these effective approaches may be less familiar or simply not preferred by respondents. The DCE enabled the clear articulation of these community priorities for evidence-based interventions that focus on the supply and promotion of affordable healthy foods within the local food environment, as well as community demand for healthier food options.
  10. Wan KS, Mustapha F, Chandran A, Ganapathy SS, Zakariah N, Ramasamy S, et al.
    Sci Rep, 2023 Oct 13;13(1):17338.
    PMID: 37833402 DOI: 10.1038/s41598-023-44564-y
    Diabetes is one of the quickest-growing global health emergencies of the twenty-first century, and data-driven care can improve the quality of diabetes management. We aimed to describe the formation of a 10-year retrospective open cohort of type 2 diabetes patients in Malaysia. We also described the baseline treatment profiles and HbA1c, blood pressure, and lipid control to assess the quality of diabetes care. We used 10 years of cross-sectional audit datasets from the National Diabetes Registry and merged 288,913 patients with the same identifying information into a 10-year open cohort dataset. Treatment targets for HbA1c, blood pressure, LDL-cholesterol, HDL-cholesterol, and triglycerides were based on Malaysian clinical practice guidelines. IBM SPSS Statistics version 23.0 was used, and frequencies and percentages with 95% confidence intervals were reported. In total, 288,913 patients were included, with 62.3% women and 54.1% younger adults. The commonest diabetes treatment modality was oral hypoglycaemic agents (75.9%). Meanwhile, 19.3% of patients had ≥ 3 antihypertensive agents, and 71.2% were on lipid-lowering drugs. Metformin (86.1%), angiotensin-converting enzyme inhibitors (49.6%), and statins (69.2%) were the most prescribed antidiabetic, antihypertensive, and lipid-lowering medications, respectively. The mean HbA1c was 7.96 ± 2.11, and 31.2% had HbA1c > 8.5%. Only 35.8% and 35.2% attained blood pressure 
  11. Sudhakaran G, Chandran A, Sreekutty AR, Madesh S, Pachaiappan R, Almutairi BO, et al.
    Molecules, 2023 Jul 12;28(14).
    PMID: 37513223 DOI: 10.3390/molecules28145350
    Diabetes Mellitus is a metabolic disease that leads to microvascular complications like Diabetic retinopathy (DR), a major cause of blindness worldwide. Current medications for DR are expensive and report multiple side effects; therefore, an alternative medication that alleviates the disease condition is required. An interventional approach targeting the vascular endothelial growth factor (VEGF) remains a treatment strategy for DR. Anti-VEGF medicines are being investigated as the main therapy for managing vision-threatening complications of DR, such as diabetic macular oedema. Therefore, this study investigated the effect of flavonoid naringenin (NG) from citrus fruits on inhibiting early DR in zebrafish. When exposed to 130 mM glucose, the zebrafish larvae developed a hyperglycaemic condition accompanied by oxidative stress, cellular damage, and lipid peroxidation. Similarly, when adult zebrafish were exposed to 4% Glucose, high glucose levels were observed in the ocular region and massive destruction in the retinal membrane. High glucose upregulated the expression of VEGF. In comparison, the co-exposure to NG inhibited oxidative stress and cellular damage and restored the glutathione levels in the ocular region of the zebrafish larvae. NG regressed the glucose levels and cellular damage along with an inhibition of macular degeneration in the retina of adult zebrafish and normalized the overexpression of VEGF as a promising strategy for treating DR. Therefore, intervention of NG could alleviate the domestication of alternative medicine in ophthalmic research.
  12. Lim LL, Abdul Aziz A, Dakin H, Buckell J, Woon YL, Roope L, et al.
    Diabetes Res Clin Pract, 2023 Nov;205:110944.
    PMID: 37804999 DOI: 10.1016/j.diabres.2023.110944
    AIMS: We determined 10-year all-cause mortality trends in diagnosed type 2 diabetes (T2D) population in West Malaysia, a middle-income country in the Western-Pacific region.

    METHODS: One million T2D people aged 40-79 registered in the National Diabetes Registry (2009-2018) were linked to death records (censored on 31 December 2019). Standardized absolute mortality rates and standardized mortality ratios (SMRs) were estimated relative to the Malaysian general population, and standardized to the 2019 registry population with respect to sex, age group, and disease duration.

    RESULTS: Overall all-cause standardized mortality rates were unchanged in both sexes. Rates increased in males aged 40-49 (annual average percent change [AAPC]: 2.46 % [95 % CI 0.42 %, 4.55 %]) and 50-59 (AAPC: 1.91 % [95 % CI 0.73 %, 3.10 %]), and females aged 40-49 (AAPC: 3.39 % [95 % CI 1.32 %, 5.50 %]). In both sexes, rates increased among those with 1) > 15 years disease duration, 2) prior cardiovascular disease, and 3) Bumiputera (Malay/native) ethnicity. The overall SMR was 1.83 (95 % CI 1.80, 1.86) for males and 1.85 (95 % CI 1.82, 1.89) for females, being higher in younger age groups and showed an increasing trend in those with either > 15 years disease duration or prior cardiovascular disease.

    CONCLUSIONS: Mortality trends worsened in certain T2D population in Malaysia.

  13. Jackson-Morris A, Sembajwe R, Mustapha FI, Chandran A, Niyonsenga SP, Gishoma C, et al.
    Glob Health Action, 2023 Dec 31;16(1):2157542.
    PMID: 36692486 DOI: 10.1080/16549716.2022.2157542
    BACKGROUND: In 2019, the World Health Organization recognised diabetes as a clinically and pathophysiologically heterogeneous set of related diseases. Little is currently known about the diabetes phenotypes in the population of low- and middle-income countries (LMICs), yet identifying their different risks and aetiology has great potential to guide the development of more effective, tailored prevention and treatment.

    OBJECTIVES: This study reviewed the scope of diabetes datasets, health information ecosystems, and human resource capacity in four countries to assess whether a diabetes phenotyping algorithm (developed under a companion study) could be successfully applied.

    METHODS: The capacity assessment was undertaken with four countries: Trinidad, Malaysia, Kenya, and Rwanda. Diabetes programme staff completed a checklist of available diabetes data variables and then participated in semi-structured interviews about Health Information System (HIS) ecosystem conditions, diabetes programme context, and human resource needs. Descriptive analysis was undertaken.

    RESULTS: Only Malaysia collected the full set of the required diabetes data for the diabetes algorithm, although all countries did collect the required diabetes complication data. An HIS ecosystem existed in all settings, with variations in data hosting and sharing. All countries had access to HIS or ICT support, and epidemiologists or biostatisticians to support dataset preparation and algorithm application.

    CONCLUSIONS: Malaysia was found to be most ready to apply the phenotyping algorithm. A fundamental impediment in the other settings was the absence of several core diabetes data variables. Additionally, if countries digitise diabetes data collection and centralise diabetes data hosting, this will simplify dataset preparation for algorithm application. These issues reflect common LMIC health systems' weaknesses in relation to diabetes care, and specifically highlight the importance of investment in improving diabetes data, which can guide population-tailored prevention and management approaches.

  14. Chee Wezen X, Chandran A, Eapen RS, Waters E, Bricio-Moreno L, Tosi T, et al.
    J Chem Inf Model, 2022 May 23;62(10):2586-2599.
    PMID: 35533315 DOI: 10.1021/acs.jcim.2c00300
    Lipoteichoic acid synthase (LtaS) is a key enzyme for the cell wall biosynthesis of Gram-positive bacteria. Gram-positive bacteria that lack lipoteichoic acid (LTA) exhibit impaired cell division and growth defects. Thus, LtaS appears to be an attractive antimicrobial target. The pharmacology around LtaS remains largely unexplored with only two small-molecule LtaS inhibitors reported, namely "compound 1771" and the Congo red dye. Structure-based drug discovery efforts against LtaS remain unattempted due to the lack of an inhibitor-bound structure of LtaS. To address this, we combined the use of a molecular docking technique with molecular dynamics (MD) simulations to model a plausible binding mode of compound 1771 to the extracellular catalytic domain of LtaS (eLtaS). The model was validated using alanine mutagenesis studies combined with isothermal titration calorimetry. Additionally, lead optimization driven by our computational model resulted in an improved version of compound 1771, namely, compound 4 which showed greater affinity for binding to eLtaS than compound 1771 in biophysical assays. Compound 4 reduced LTA production in S. aureus dose-dependently, induced aberrant morphology as seen for LTA-deficient bacteria, and significantly reduced bacteria titers in the lung of mice infected with S. aureus. Analysis of our MD simulation trajectories revealed the possible formation of a transient cryptic pocket in eLtaS. Virtual screening (VS) against the cryptic pocket led to the identification of a new class of inhibitors that could potentiate β-lactams against methicillin-resistant S. aureus. Our overall workflow and data should encourage further drug design campaign against LtaS. Finally, our work reinforces the importance of considering protein conformational flexibility to a successful VS endeavor.
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