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Fulltext Editorial: Integrated omics approaches in the understanding of host-pathogen interactions

Al-Maleki AR, Braima K, Rosli NA

Front Cell Infect Microbiol, 2023;13:1215104.
PMID: 37305425 DOI: 10.3389/fcimb.2023.1215104
A review of natural polysaccharides for drug delivery applications: Special focus on cellulose, starch and glycogen

Gopinath V, Saravanan S, Al-Maleki AR, Ramesh M, Vadivelu J

Biomed Pharmacother, 2018 Nov;107:96-108.
PMID: 30086465 DOI: 10.1016/j.biopha.2018.07.136

Natural polysaccharides are renewable with a high degree of biocompatibility, biodegradability, and ability to mimic the natural extracellular matrix (ECM) microenvironment. Comprehensive investigations of polysaccharides are essential for our fundamental understanding of exploiting its potential as bio-composite, nano-conjugate and in pharmaceutical sectors. Polysaccharides are considered to be superior to other polymers, for its ease in tailoring, bio-compatibility, bio-activity, homogeneity and bio-adhesive properties. The main focus of this review is to spotlight the new advancements and challenges concerned with surface modification, binding domains, biological interaction with the conjugate including stability, polydispersity, and biodegradability. In this review, we have limited our survey to three essential polysaccharides including cellulose, starch, and glycogen that are sourced from plants, microbes, and animals respectively are reviewed. We also present the polysaccharides which have been extensively modified with the various types of conjugates for combating last-ditch pharmaceutical challenges.
Revisiting oral thrush in South-East Asian patients: A review of published studies (2000-2020)

Karajacob AS, Al-Maleki AR, Tay ST

J Oral Pathol Med, 2022 Jan;51(1):98-105.
PMID: 34859509 DOI: 10.1111/jop.13266

BACKGROUND: Oral thrush, a clinical condition due to an overgrowth of Candida yeasts in the oral cavity, is prominent in patients with immunosuppression. As recent updates on oral thrush in South-East Asian (SEA) countries are lacking, this review aimed to address the epidemiology, clinical features and distribution of Candida species, based on published studies in SEA countries over the last two decades.
METHODS: Published studies on oral candidiasis (2000-2020) were retrieved from PubMed, Scopus, ISI Web of Science and Google Scholar databases to provide information on the incidence and factors affecting oral thrush cases in SEA countries.
RESULTS: A total of 22 cross-sectional studies involving 3697 subjects from five SEA countries were reviewed in this study. The most frequently reported population were human immunodeficiency virus (HIV)-infected patients. The overall incidence rates amongst HIV-infected patients ranged from 20.7% to 97.0%, while incidence rates ranging from 0% to 72.7% were recorded for non-HIV-infected populations. Pseudomembranous candidiasis and erythematous candidiasis were the most common clinical presentations of oral thrush lesions. Candida albicans was the most common species identified in SEA studies. As oral thrush assessments were made merely based on clinical diagnosis, culture results were not available for most studies.
CONCLUSION: This review highlights that most studies reporting on oral candidiasis in SEA countries were based on HIV-positive patients. Data are still lacking on oral candidiasis amongst non-HIV immunocompromised and immunocompetent patients. Increasing awareness on the diagnosis, treatment and consequences of this infection, and improved laboratory methods are essential for the management of oral candidiasis in this region.
Corrigendum to "Synthesis and evaluation of antibacterial activity of transition metal-oleoyl amide complexes" [Bioorganic Chem. 140 (2023) 106786]

Farhan N, Al-Maleki AR, Sarih NM, Yahya R

Bioorg Chem, 2023 Dec;141:106915.
PMID: 37863715 DOI: 10.1016/j.bioorg.2023.106915
Synthesis and evaluation of antibacterial activity of transition metal-oleoyl amide complexes

Farhan N, Al-Maleki AR, Sarih NM, Yahya R

Bioorg Chem, 2023 Nov;140:106786.
PMID: 37586131 DOI: 10.1016/j.bioorg.2023.106786

Recent studies show that some metal ions, injure microbial cells in various ways due to membrane breakdown, protein malfunction, and oxidative stress. Metal complexes are suited for creating novel antibacterial medications due to their distinct mechanisms of action and the variety of three-dimensional geometries they can acquire. In this Perspective, the present study focused on new antibacterial strategies based on metal oleoyl amide complexes. Thus, oleoyl amides ligand (fatty hydroxamic acid and fatty hydrazide hydrate) with the transition metal ions named Ag (I), Co (II), Cu (II), Ni (II) and Sn (II) complexes were successfully synthesized in this study. The metals- oleoyl amide were characterized using elemental analysis, and fourier transforms infrared (FTIR) spectroscopy. The antibacterial effect of metals- oleoyl amide complexes was investigated for Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus) by analysing minimum inhibitory concentration (MIC), minimal bactericidal concentration (MBC), and scanning electron microscopy (SEM). The results showed that metal-oleoyl amide complexes have high antibacterial activity at low concentrations. This study inferred that metal oleoyl amide complexes could be utilised as a promising therapeutic antibacterial agent.
Enhanced intracellular survival and epithelial cell adherence abilities of Burkholderia pseudomallei morphotypes are dependent on differential expression of virulence-associated proteins during mid-logarithmic growth phase

Al-Maleki AR, Mariappan V, Vellasamy KM, Shankar EM, Tay ST, Vadivelu J

J Proteomics, 2014 Jun 25;106:205-20.
PMID: 24742602 DOI: 10.1016/j.jprot.2014.04.005

Colony morphology variation is a characteristic of Burkholderia pseudomallei primary clinical isolates, associated with variations in expression of virulence factors. Here, we performed comparative investigations on adhesion, invasion, plaque-forming abilities and protein profiles of B. pseudomallei wild-type (WT) and a small colony variant (SCV). The percentage of SCV adherence to A549 cells was significantly higher (2.73%) than WT (1.91%). In contrast, WT was significantly more efficient (0.63%) than SCV (0.31%) in invasiveness and in inducing cellular damage. Using 2-DE and MALDI TOF/TOF, 263 and 258 protein spots were detected in WT and SCV, respectively. Comparatively, 49 proteins were differentially expressed in SCV when compared with WT. Of these, 31 proteins were up-regulated, namely, nucleoside diphosphate kinase (Ndk), phosphoglycerate kinase (Pgk), thioredoxin (TrxA), putative ferritin DPS-family DNA-binding protein (DPS) and oxidoreductase (AhpC) that are known to be involved in adhesion, intracellular survival and persistence. However, among the 18 down-regulated proteins, enolase (Eno), elongation factor (EF-Tu) and universal stress-related proteins were associated with invasion and virulence. Differences observed in these protein profiles provide ample clues to their association with the morphotypic and phenotypic characteristics of colony variants, providing additional insights into the potential association of B. pseudomallei colony morphotypes with disease pathogenesis.
Transcriptome analysis of Burkholderia pseudomallei SCV reveals an association with virulence, stress resistance and intracellular persistence

Al-Maleki AR, Vellasamy KM, Mariappan V, Venkatraman G, Tay ST, Vadivelu J

Genomics, 2020 01;112(1):501-512.
PMID: 30980902 DOI: 10.1016/j.ygeno.2019.04.002

Differences in expression of potential virulence and survival genes were associated with B. pseudomallei colony morphology variants. Microarray was used to investigate B. pseudomallei transcriptome alterations among the wild type and small colony variant (SCV) pre- and post-exposed to A549 cells. SCV pre- and post-exposed have lower metabolic requirements and consume lesser energy than the wild type pre- and post-exposed to A549. However, both the wild type and SCV limit their metabolic activities post- infection of A549 cells and this is indicated by the down-regulation of genes implicated in the metabolism of amino acids, carbohydrate, lipid, and other amino acids. Many well-known virulence and survival factors, including T3SS, fimbriae, capsular polysaccharides and stress response were up-regulated in both the wild type and SCV pre- and post-exposed to A549 cells. Microarray analysis demonstrated essential differences in bacterial response associated with virulence and survival pre- and post-exposed to A549 cells.
Profiling of gene expression in methicillin-resistant Staphylococcus aureus in response to cyclo-(L-Val-L-Pro) and chloramphenicol isolated from Streptomyces sp., SUK 25 reveals gene downregulation in multiple biological targets

Zin NM, Al-Shaibani MM, Jalil J, Sukri A, Al-Maleki AR, Sidik NM

Arch Microbiol, 2020 Oct;202(8):2083-2092.
PMID: 32494868 DOI: 10.1007/s00203-020-01896-x

Chloramphenicol (CAP) and cyclo-(L-Val-L-Pro) were previously isolated from Streptomyces sp., SUK 25 which exhibited a high potency against methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to profile gene expression of MRSA treated with CAP and cyclo-(L-Val-L-Pro) compounds using DNA microarray. Treatment of MRSA with CAP resulted in upregulation of genes involved in protein synthesis, suggesting the coping mechanism of MRSA due to the inhibition of protein synthesis effect from CAP. Most upregulated genes in cyclo-(L-Val-L-Pro) were putative genes with unknown functions. Interestingly, genes encoding ribosomal proteins, cell membrane synthesis, DNA metabolism, citric acid cycle and virulence were downregulated in MRSA treated with cyclo-(L-Val-L-Pro) compound, suggesting the efficacy of this compound in targeting multiple biological pathways. Contrary to CAP, with only a single target, cyclo-(L-Val-L-Pro) isolated from this study had multiple antimicrobial targets that can delay antibiotic resistance and hence is a potential antimicrobial agent of MRSA.
Salivary and serum cathelicidin LL-37 levels in subjects with rheumatoid arthritis and chronic periodontitis

Cheah CW, Al-Maleki AR, Vadivelu J, Danaee M, Sockalingam S, Baharuddin NA, et al.

Int J Rheum Dis, 2020 Oct;23(10):1344-1352.
PMID: 32743970 DOI: 10.1111/1756-185X.13919

INTRODUCTION: Rheumatoid arthritis (RA) is associated with chronic periodontitis (CP) due to shared risk factors, immuno-genetics and tissue destruction pathways. Human cathelicidin LL-37 has been suggested as a possible mechanistic link for these diseases. This study investigated the levels of salivary and serum LL-37 in subjects with RA and CP and their correlation with disease parameters.
METHOD: Subjects were allocated into RA (n = 49) or non-RA (NRA) (n = 55) groups, where 3 subgroups were further established; chronic periodontitis (CP), gingivitis (G) and periodontal health (H). Demographic and periodontal parameters were collected. Rheumatology data were obtained from hospital records. Serum and salivary LL-37 levels were measured using enzyme-linked immunosorbent assay and compared for all groups.
RESULTS: For salivary LL-37, RA-CP was significantly higher than NRA-G and NRA-H (P = .047). For serum LL-37, all RA and NRA-CP were significantly higher than NRA-G and NRA-H (P = .024). Salivary LL-37 correlated negatively with clinical attachment loss (CAL) (P = .048), but positively with erythrocyte sedimentation rate (ESR) in RA-H (P = .045). Serum LL-37 showed positive correlation with ESR (P = .037) in RA-G, with C-reactive protein (P = .017) in RA-H, but negative correlation with number of teeth (P = .002) in NRA-CP. Rheumatology data correlated positively with periodontal parameters in RA-CP group.
CONCLUSION: NRA-CP subjects with high serum LL-37 should receive comprehensive periodontal therapy. Positive correlation between rheumatology data and periodontal parameters showed that RA disease stability may be obtained by assessing the periodontal condition. Periodontal therapy is necessary to compliment RA treatment to achieve optimum outcome for RA patients with concurrent CP.
Polymorphism of virulence genes and biofilm associated with in vitro induced resistance to clarithromycin in Helicobacter pylori

Rosli NA, Al-Maleki AR, Loke MF, Chua EG, Alhoot MA, Vadivelu J

Gut Pathog, 2023 Oct 28;15(1):52.
PMID: 37898785 DOI: 10.1186/s13099-023-00579-4

BACKGROUND: Clarithromycin-containing triple therapy is commonly used to treat Helicobacter pylori infections. Clarithromycin resistance is the leading cause of H. pylori treatment failure. Understanding the specific mutations that occur in H. pylori strains that have evolved antibiotic resistance can help create a more effective and individualised antibiotic treatment plan. However, little is understood about the genetic reprogramming linked to clarithromycin exposure and the emergence of antibiotic resistance in H. pylori. Therefore, this study aims to identify compensatory mutations and biofilm formation associated with the development of clarithromycin resistance in H. pylori. Clarithromycin-sensitive H. pylori clinical isolates were induced to develop clarithromycin resistance through in vitro exposure to incrementally increasing concentration of the antibiotic. The genomes of the origin sensitive isolates (S), isogenic breakpoint (B), and resistant isolates (R) were sequenced. Single nucleotide variations (SNVs), and insertions or deletions (InDels) associated with the development of clarithromycin resistance were identified. Growth and biofilm production were also assessed.
RESULTS: The S isolates with A2143G mutation in the 23S rRNA gene were successfully induced to be resistant. According to the data, antibiotic exposure may alter the expression of certain genes, including those that code for the Cag4/Cag protein, the vacuolating cytotoxin domain-containing protein, the sel1 repeat family protein, and the rsmh gene, which may increase the risk of developing and enhances virulence in H. pylori. Enhanced biofilm formation was detected among R isolates compared to B and S isolates. Furthermore, high polymorphism was also detected among the genes associated with biofilm production.
CONCLUSIONS: Therefore, this study suggests that H. pylori may acquire virulence factors while also developing antibiotic resistance due to clarithromycin exposure.
Fulltext Altered Proteome of Burkholderia pseudomallei Colony Variants Induced by Exposure to Human Lung Epithelial Cells

Al-Maleki AR, Mariappan V, Vellasamy KM, Tay ST, Vadivelu J

PLoS One, 2015;10(5):e0127398.
PMID: 25996927 DOI: 10.1371/journal.pone.0127398

Burkholderia pseudomallei primary diagnostic cultures demonstrate colony morphology variation associated with expression of virulence and adaptation proteins. This study aims to examine the ability of B. pseudomallei colony variants (wild type [WT] and small colony variant [SCV]) to survive and replicate intracellularly in A549 cells and to identify the alterations in the protein expression of these variants, post-exposure to the A549 cells. Intracellular survival and cytotoxicity assays were performed followed by proteomics analysis using two-dimensional gel electrophoresis. B. pseudomallei SCV survive longer than the WT. During post-exposure, among 259 and 260 protein spots of SCV and WT, respectively, 19 were differentially expressed. Among SCV post-exposure up-regulated proteins, glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase (CbbA) and betaine aldehyde dehydrogenase were associated with adhesion and virulence. Among the down-regulated proteins, enolase (Eno) is implicated in adhesion and virulence. Additionally, post-exposure expression profiles of both variants were compared with pre-exposure. In WT pre- vs post-exposure, 36 proteins were differentially expressed. Of the up-regulated proteins, translocator protein, Eno, nucleoside diphosphate kinase (Ndk), ferritin Dps-family DNA binding protein and peptidyl-prolyl cis-trans isomerase B were implicated in invasion and virulence. In SCV pre- vs post-exposure, 27 proteins were differentially expressed. Among the up-regulated proteins, flagellin, Eno, CbbA, Ndk and phenylacetate-coenzyme A ligase have similarly been implicated in adhesion, invasion. Protein profiles differences post-exposure provide insights into association between morphotypic and phenotypic characteristics of colony variants, strengthening the role of B. pseudomallei morphotypes in pathogenesis of melioidosis.
Fulltext Exposure of Helicobacter pylori to clarithromycin in vitro resulting in the development of resistance and triggers metabolic reprogramming associated with virulence and pathogenicity

Rosli NA, Al-Maleki AR, Loke MF, Tay ST, Rofiee MS, Teh LK, et al.

PLoS One, 2024;19(3):e0298434.
PMID: 38446753 DOI: 10.1371/journal.pone.0298434

In H. pylori infection, antibiotic-resistance is one of the most common causes of treatment failure. Bacterial metabolic activities, such as energy production, bacterial growth, cell wall construction, and cell-cell communication, all play important roles in antimicrobial resistance mechanisms. Identification of microbial metabolites may result in the discovery of novel antimicrobial therapeutic targets and treatments. The purpose of this work is to assess H. pylori metabolomic reprogramming in order to reveal the underlying mechanisms associated with the development of clarithromycin resistance. Previously, four H. pylori isolates were induced to become resistant to clarithromycin in vitro by incrementally increasing the concentrations of clarithromycin. Bacterial metabolites were extracted using the Bligh and Dyer technique and analyzed using metabolomic fingerprinting based on Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-Q-ToF-MS). The data was processed and analyzed using the MassHunter Qualitative Analysis and Mass Profiler Professional software. In parental sensitivity (S), breakpoint isolates (B), and induced resistance isolates (R) H. pylori isolates, 982 metabolites were found. Furthermore, based on accurate mass, isotope ratios, abundances, and spacing, 292 metabolites matched the metabolites in the Agilent METLIN precise Mass-Personal Metabolite Database and Library (AM-PCDL). Several metabolites associated with bacterial virulence, pathogenicity, survival, and proliferation (L-leucine, Pyridoxone [Vitamine B6], D-Mannitol, Sphingolipids, Indoleacrylic acid, Dulcitol, and D-Proline) were found to be elevated in generated resistant H. pylori isolates when compared to parental sensitive isolates. The elevated metabolites could be part of antibiotics resistance mechanisms. Understanding the fundamental metabolome changes in the course of progressing from clarithromycin-sensitive to breakpoint to resistant in H. pylori clinical isolates may be a promising strategy for discovering novel alternatives therapeutic targets.
Fulltext Burkholderia vaccines: are we moving forward?

Choh LC, Ong GH, Vellasamy KM, Kalaiselvam K, Kang WT, Al-Maleki AR, et al.

Front Cell Infect Microbiol, 2013;3:5.
PMID: 23386999 DOI: 10.3389/fcimb.2013.00005

The genus Burkholderia consists of diverse species which includes both "friends" and "foes." Some of the "friendly" Burkholderia spp. are extensively used in the biotechnological and agricultural industry for bioremediation and biocontrol. However, several members of the genus including B. pseudomallei, B. mallei, and B. cepacia, are known to cause fatal disease in both humans and animals. B. pseudomallei and B. mallei are the causative agents of melioidosis and glanders, respectively, while B. cepacia infection is lethal to cystic fibrosis (CF) patients. Due to the high rate of infectivity and intrinsic resistance to many commonly used antibiotics, together with high mortality rate, B. mallei and B. pseudomallei are considered to be potential biological warfare agents. Treatments of the infections caused by these bacteria are often unsuccessful with frequent relapse of the infection. Thus, we are at a crucial stage of the need for Burkholderia vaccines. Although the search for a prophylactic therapy candidate continues, to date development of vaccines has not advanced beyond research to human clinical trials. In this article, we review the current research on development of safe vaccines with high efficacy against B. pseudomallei, B. mallei, and B. cepacia. It can be concluded that further research will enable elucidation of the potential benefits and risks of Burkholderia vaccines.
Helicobacter pylori outer inflammatory protein A (OipA) suppresses apoptosis of AGS gastric cells in vitro

Al-Maleki AR, Loke MF, Lui SY, Ramli NSK, Khosravi Y, Ng CG, et al.

Cell. Microbiol., 2017 12;19(12).
PMID: 28776327 DOI: 10.1111/cmi.12771

Outer inflammatory protein A (OipA) is an important virulence factor associated with gastric cancer and ulcer development; however, the results have not been well established and turned out to be controversial. This study aims to elucidate the role of OipA in Helicobacter pylori infection using clinical strains harbouring oipA "on" and "off" motifs. Proteomics analysis was performed on AGS cell pre-infection and postinfection with H. pylori oipA "on" and "off" strains, using liquid chromatography/mass spectrometry. AGS apoptosis and cell cycle assays were performed. Moreover, expression of vacuolating cytotoxin A (VacA) was screened using Western blotting. AGS proteins that have been suggested previously to play a role or associated with gastric disease were down-regulated postinfection with oipA "off" strains comparing to oipA "on" strains. Furthermore, oipA "off" and ΔoipA cause higher level of AGS cells apoptosis and G0/G1 cell-cycle arrest than oipA "on" strains. Interestingly, deletion of oipA increased bacterial VacA production. The capability of H. pylori to induce apoptosis and suppress expression of proteins having roles in human disease in the absence of oipA suggests that strains not expressing OipA may be less virulent or may even be protective against carcinogenesis compared those expressing OipA. This potentially explains the higher incidence of gastric cancer in East Asia where oipA "on" strains predominates.

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