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PRELIMINARY SCHEDULE OF TALKS

SYMPOSIUM PROGRAMME
* Click on speakers and presenters name to view abstract
DAY 1: 18th MARCH 2009
Auditorium, Asia-Europe Institute (AEI), University Of Malaya

07:30 - 08:15 Arrival and registration of participants
08:30 - 08:50 OPENING CEREMONY
Chairperson: Associate Professor Dr Jamal I-Ching Sam

Welcome Address by BHC, Malaysia:
Mr Trevor Lewis
Director of Trade and Investment, BHC.

Welcome Address & Official Launching by:
Professor Dato’ Dr. Mohd Jamil Maah
Deputy Vice-Chancellor (Research & Innovation), UM.

Session 1 Chairperson: Professor Dr Sazaly Abu Bakar
08:50 – 09:25 Speaker 1
Professor Dr. Rahmah Mohamed, Universiti Kebangsaan Malaysia
“Molecular Biology of Burkholderia Pseudomallei”

09:25 – 10:00 Speaker 2


Abstract: Data Base Mining tools have been developed to aid the search for small molecule compounds that will bind and inhibit target proteins. A range of different protein targets are being investigated including allosteric proteins of the glycolytic pathway as well as kinases and other effector and inhibitor proteins that control cell proliferation. In most cases the 3D structure of the target is known and a druggable pocket can be identified for docking studies. We have developed a searchable database of 4 million commercially available compounds (EDULISS) which is used in a variety of types of searches including our docking program LIDAEUS that is implemented on BlueGene. Potential hits are screened using various biophysical methods.

10:00 – 10:30 TEA BREAK
Session 2 Chairperson: Professor Dr Raha Abdul Rahim
10:30 – 11:05 Speaker 3


Abstract: Sialdiases, or neuraminidases, catalyse the removal of sialic acid from the surface of cells. Sialic acid is a negatively-charged carbohydrate that decorates various glycol-conjugates, and its terminal location has been exploited by a number of pathogens for attachment during initial infection. Sialic acid can also be removed by pathogens to reveal other cryptic carbohydrate receptors for cell attachment, and the released sugar can be used by certain bacteria as an energy source. The influenza virus neuraminidase is the best studied member of the sialidase superfamiliy, the structure of which has been used for the development of Tamiflu and Relenza, drugs used for the treatment of influenza. My own laboratory has been studying the structural biology of sialidases from paramyxoviruses and a number of bacteria. Studies on the paramyxovirus hemagglutinin-neuraminidase enabled the development of an inhibitor that protects mice from a lethal paramyxovirus, and has promise in the treatment of human parainfluenza. The Streptococcus pneumoniae genome encodes three sialdiases, and we have recently determined the structures of two of these, NanA and NanB. Gene knockout experiments have shown that these sialidases are crucial for bacterial colonisation in the respiratory tract and in blood, and hence may be good drug targets. Pseudomonas aeruginosa, another respiratory pathogen, is a particular problem for cystic fibrosis patients where it can form biofilm in the lungs. Mouse experiments have shown that knocking out the sialidase of P. aeruginosa severely reduces biofilm formation. We have recently determined the structure of this sialidase that shows an unusual trimeric fold with alterations in the active site that suggest that sialic acid is not the substrate, but rather pseudaminic acid, another carbohydrate that decorates the flagella and pili of certain bacteria. We have embarked on the structure-based development of inhibitors of these bacterial sialidases.

11:05 – 11:40 Speaker 4


Abstract: Membrane-associated proteins are of central importance in the regulation of signal transduction, vesicular transport, receptor recycling and many other essential processes in biology. Certain of these proteins (e.g Ras, Src, Rab and MARCKS), possess C or N-terminal lipophilic groups (such as myristoyl or palmitoyl) that insert into the hydrophobic core of a lipid bilayer. Elsewhere in these proteins, clusters of basic amino acids bind to negatively charged components of the cell membrane. The combination is known as the “myristoyl-electrostatic switch”. It has been mimicked with synthetic peptides which, when attached to therapeutic proteins, enable their localisation on mammalian cell membranes and thereby the therapeutic manipulation of cell surface phenotype. This process is known as cytotopic modification and has a wide variety of applications such as protection of the vasculature of solid organs prior to transplantation and in cell therapy. These will be outlined briefly. Bacteria have a distinct membrane composition with components not found in mammalian cells. We have developed a strategy to target the glycopeptide antibiotic vancomycin to bacterial cell membranes. We sought firstly to increase the local concentration at the site of action (cell wall synthesis), secondly to increase the affinity for the target enzyme and thirdly to access and inhibit other membrane-bound bacterial targets.

Biased combinatorial libraries of peptides based on the effector sequences of myristoyl-electrostatic switch proteins were ligated to libraries of membrane-insertive hydrophobic elements. This approach used an easily prepared common C-terminal vancomycin derivative which permitted facile coupling of these amphipathic peptides The conjugates were highly active against a broad range of bacteria, including vancomycin-resistant enterococci (VRE), methicillin-resistant S. aureus (EMRSA) and glycopeptide intermediate-resistance S. aureus (GISA). The strategy allowed for rapid optimization of anti-bacterial activity with enhanced affinities for bacterial membranes compared to eukaryotic ones and led to potent broad spectrum compounds that were only weakly haemolytic against mammalian erythrocytes but lytic to bacteria. Mechanistic studies showed that the compounds were bactericidal rather than simply bacteriostatic and that enzymes other than bacterial transpeptidase appeared to be targeted resulting in an inhibition profile more similar to ramoplanin than vancomycin (the compounds were shown also to inhibit the intracellular production of the peptidoglycan precursor Lipid II). Membrane localization was a key determinant of potency and toxicity. Lead compounds have been identified and further development of these agents is planned.



11:40 – 12:15 Speaker 5
Associate Professor Dr. Mariana Nor Shamsudin, Universiti Putra Malaysia
“Molecular probing of marine based antimicrobials with synergistic ability in inhibiting MRSA”

12:15 – 12:50 Speaker 6


Abstract: The international surge in infectious disease with attendant human suffering and morbidity has significantly raised research activity in the area of anti-infectives. Defensins, a major family of natural peptides found in mammals and known for their broad spectrum antimicrobial activity has earned them the name of “natural antibiotics”. As a component of the innate immune system which protects mucosal surfaces such as the front of the eye, mouth and lungs as a first line of defense against infection. In humans, there are six characterized alpha-defensins, human neutrophil peptides (HNP1 to HNP6) and four beta-defensins (HBD1 to HBD4). Based on the spatial distribution of the cysteine linkages, the mammalian defensins can de divided into two major groups termed alpha- and beta-defensins which are produced in neutrophils and mucosal surface epithelial cells of humans. However, defensins have some limitations such as toxicity at higher concentrations, expensive to synthesize, properties that are not optimized for human application. At the Singapore Eye Research Institute we have developed a multi-disciplinary approach to engineering new anti-microbial peptides. Short-branched and linear molecules with moderate levels of hydrophobicity and net charge have been found to have little or no cytotoxicity to host mucosal epithelial cells, while exhibiting low MIC values. In addition, these have been shown to be effective toward fungus, as well as clinical strains of Pseudomonas some of which are gentamicin resistant and a MRSA. Recent studies suggest that defensins may have much broader functions, acting as chemo-attractant agents for monocytes and dendritic cells. Therefore we have examined the immunomodulatory properties of the native peptides and defensins analogues. A possible advantage of defensins over conventional antibiotics is their positive participation in wound healing. Defensins stimulate the proliferation of fibroblasts and epithelial cells, increase the expression of genes involved in wound healing responses, further suggesting that the function of defensins in the host system may be well beyond direct killing of microorganisms.

01:00 – 02:30 LUNCH BREAK
Session 3 Chairperson: Associate Professor Dr Mariana Nor Shamsudin
02:30 – 03:05 Speaker 7


Abstract: The food grade Lactococcus lactis is a potential vector to be used as a live vehicle for the delivery of heterologous proteins for vaccine production and pharmaceutical purposes. Here, we present some work carried out in our laboratory on the development of heterologous protein expression systems in L. lactis including plasmid isolation and characterization, vector development, recombinant vaccine models and a novel surface display mechanism. Lactococcus spp were isolated from various sources and identified by biochemical and 16S rRNA sequence analyses. Species-specific primers were designed according to published sequence for the identification of L. lactis and the amplified regions sequenced. Eight positive isolates were cultured and used for further manipulations. Several small plasmids from the L. lactis isolates were characterized, including plasmids pAJ01 and pAR141. The rep gene of pAJ01 and the complete 1594 base pair nucleotide sequence of pAR141 were determined. Sequence analysis showed that the CopG and replication initition protein RepB appeared as a single operon. A small countertranscribed RNA (ctRNA) coding region was found between the copG and repB genes of pAR141. The dso and sso of RCR plasmids were also identified, suggesting that pAR141 replicates by a rolling circle mode. These plasmids were then developed into shuttle and expression vectors. Several peptide regions of the pathogenic microbes and virus (Aeromonas sp, Vibrio sp and enterovirus,) were identified and cloned into vectors utilizing constitutive and inducible promoters. These were expressed in L. lactis and delivered to the respective hosts via oral and/or intraperitoneal injection routes. Immunological and challenge studies indicated positive and protective responses. A novel display system was developed utilizing a 225-bp single repeat sequence of the cell wall-binding protein region of the AcmA Lactococcal protein. The new system designed for cell surface display of recombinant proteins on L. lactis was evaluated for the expression and display of A1 and A3 regions of the VP1 of enterovirus 71 (EV71). Whole cell ELISA postulated successful display of the epitopes. Western blot analysis showed the elicitation of antibodies in mice orally fed with L. lactis displaying the A1 and A3 epitopes. Based on the results obtained, this system was shown to be able to elicit antibody response in its host.

03:05 – 03:40 Speaker 8


Abstract: Pili are adhesive multi-subunit fibres assembled on the surface of many pathogenic bacteria. In several systems such as E. coli and Salmonella enterica this occurs via the chaperone-usher pathway: in the periplasm, a chaperone donates a beta-strand to a pilus subunit to complement its incomplete immunoglobulin-like fold; this is replaced at the outer membrane with a beta-strand formed from the N-terminal extension (Nte) of an incoming pilus subunit. Molecular simulations demonstrated that this reaction occurs through an intermediate; and that this intermediate occurs because a binding pocket is present (or forms dynamically) to accept the Nte while the chaperon has not been yet released. I will show further evidence of the importance of dynamics in tuning the affinities of the various subunits in the case of Pap and Fim pili from uropathogenic E. coli. Such affinities are also responsible for the precise ordering of subunits in such pili and the growth termination which in turn are important for their function. These results altogether suggest that pilus growth could be hindered by developing antibacterial agents which target the dynamical correlations in the subunit-chaperon complexes.

03:40 – 04:15 TEA BREAK
Session 4 Chairperson: Professor Malcolm Walkinshaw
04:15 – 04:50 Speaker 9


Abstract: The talk will describe recent progress in the application of fragment-based methods to develop biologically active small molecules. The approach involves using a range of biophysical and structural techniques to identify small molecular fragments that bind to a target protein with low affinity but high ligand efficiency. There then follows iterative cycles of chemical synthesis and structure-based rational design as the fragments are elaborated to increase affinity and specificity. There will be a particular focus on finding fragments and using them as starting points to develop enzyme inhibitors against Mycobacterium tuberculosis. This work fits as part of joint international efforts to develop new lead compounds to aid TB drug discovery.

04:50 – 05:25 Speaker 10


Abstract: There are two broad strategies for the control of bacterial infection, either (a) kill the organism or (b) attenuate virulence such the infecting organism fails to adapt to the host environment and can be cleared by the host defenses. Anti-virulence agents offer several potential advantages including expanding the repertoire of bacterial targets, preserving the host micro flora and exerting less selective pressure, which may result in decreased resistance. In many pathogens, virulence is co-ordinately controlled via sophisticated global regulatory systems such as quorum sensing. This is usually defined as cell population density dependent gene regulation and is mediated via self-generated extracellular signal molecules. These low molecular weight compounds or ‘auto inducers’ activate or repress QS target genes once a critical threshold concentration of signal has been reached. The key components of any QS ‘module’ are the QS signal synthase, the signal receptor and the signal molecule. QS systems offer multiple targets for chemical intervention through the blockade of QS signal synthesis, QS signal molecule degradation or inhibition of QS signal reception. Natural products and synthetic signal molecule analogues have been identified as QS inhibitors and these offer considerable promise for the treatment of infections caused by multi-antibiotic resistant bacteria.

~ End of Day 1 ~

DAY 2: 19th MARCH 2009
Biotechnology, Faculty of Medicine

Chairperson: Professor Dr Ngeow Yun Fong
08:30 – 08:45 Presentation 1


Abstract: HIV is among the most genetically variable human viruses and is characterized by high rates of mutation, viral replication and recombination. In addition to pure subtypes, HIV-1 circulating recombinant forms (CRFs) are generated by recombination between distinct subtypes and/or other CRFs and are spreading at epidemic rates in various parts of the world. However, the molecular evolution and epidemic history of HIV-1 recombinants have not been fully explored – possibly due to a lack of statistical methods that can reliably reconstruct the evolutionary dynamics of genetic sequences with recombination. In Southeast Asia, HIV-1 CRF33_01B is a recently emerged recombinant descended from CRF01_AE and subtype B. Thought to be originated in Malaysia, CRF33_01B has been expanding and found commonly among HIV-infected individuals from various risk groups. By incorporating a relaxed clock Bayesian phylogenetic model into a classical framework of reticulate evolution, we attempt to assess the age of the putative recombination event that gave rise to CRF33_01B. This proof-of-concept approach provides a practical and robust evolutionary biology method for estimating the “date of birth” of recombinant lineages. On the other hand, CRF08_BC and CRF07_BC are two highly prevalent HIV strains that are circulating in Asia – causing hundreds of thousands of infections in China. Despite the massive epidemic impact, the specific times of emergence and divergence of CRF08_BC, CRF07_BC and their putative subtype C parental lineages remain uninvestigated and unknown. Outside mainland China, CRF07_BC is also associated with a dramatic increase of HIV cases in Taiwan. Here, we investigate the spatial and temporal spread of CRF08_BC and CRF07_BC, and provide a timescale for the eastwards migration of HIV/AIDS in East Asia. Finally, we highlight the significance of HIV-1 evolutionary history upon viral epidemiology, dispersal and vaccinology.

08:45 – 09:00 Presentation 2


Abstract: Gram negative bacteria communicate via the production and sensing of N-acyl-homoserine lactone (AHL) signal molecules in relation to its population density. This bacterial cell-to-cell communication is known as quorum sensing (QS) which regulates gene expression that controls a broad range of physiological activities, in response to extracellular signals. Quorum quenching owing to enzymatic degradation of AHL molecules was first reported in the Gram-positive Bacillus species which inactivates AHLs via lactonase activity. Subsequently, acylase from Pseudomonas aeruginosa PAO1 has been reported to hydrolyse the N-acyl side chain from the lactone ring. Malaysia has been recognized as one of the mega-biodiversity countries, in this work, we explored the rain forest soil, nepenthes pitcher cup digestive fluid for the isolation of quorum quenching bacteria. Here we describe the isolation of novel quorum quenching bacteria that showed broad quorum quenching activity i.e. they could degrade 3-unsubstituted-N-acylhomoserine lactones, 3-hydroxyl-N-acylhomoserine lactones and 3-oxo-N-acylhomoserine lactones albeit with different specificity. These bacterial isolates may act in concert to degrade the AHLs that they encounter in their natural habitat. This may confer them competitive advantage when competing against the bacteria that use QS to regulate their genes expression. These bacterial isolates may represent a novel bio-control agent. In this work, we present the novel selection medium and procedures that facilitates rapid isolation and selection of quorum quenching bacteria from unique habitats. We also report here the novel strains that show quorum quenching activities as confirmed by rapid resolution liquid chromatography.

09:00 – 09:15 Presentation 3
Professor Dr Sazaly Abu Bakar, University of Malaya
“Antibiotic Resistance of Acinetobacter: From hospital to space”

09:15 – 10:45 Round Table Discussion

10:45 – 11:00 TEA BREAK
11:00 – 11:30 A tour to Proteomic Laboratory

11:30 – 12:00 A tour to Pharmacology Laboratory

~ End of Day 2 ~
2009 Developed by Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Malaysia