Agenda

Date

June 22-23, 2020

Location

Zurich, Switzerland




Conference Agenda

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Keynote Session:

Oral Session 1:

  • Microorganisms Producing Antibiotics | Veterinary Antibiotics | Toxicity of Antibacterial Drugs | Industrial Scope of Antibiotics
Meetings International - Antibiotics-2020 Conference Keynote Speaker Esther van der Werf photo

Esther van der Werf

Louis Bolk Institute, Netherlands

Title: The mighty human microbiome: a key to solving the problem of AMR in primary care?

Biography:

I am a senior epidemiologist and joined The Louis Bolk Institute per September 2019 as Program Manager Nutrition & Health to continue my research on Integrative medicine and antimicrobial stewardship. I obtained my PhD from Erasmus University Rotterdam (2006) in the Netherlands and subsequently worked at University of Medical Centre Utrecht and University of Applied Sciences Leiden, before coming to the Center of Academic Primary Care of the University of Bristol in 2015. From August 2018 to August 2019 I have been working at the School of Medicine of Taylor's University, Kuala Lumpur, Malaysia.
I have 20 years’ experience of research (over 40 peer-review publications: H-index=18) and project management (Randomised clinical trials and observational studies). My current work has a strong focus on health promotion, prevention and integrative medicine.

Abstract:

The human microbiome is overly exposed to antibiotics, due, not only to their medical use, but also to their utilization in farms. In the last decade interest in the effect of antibiotic therapy on the host microbiota has increased, and new technologies are beginning to uncover the complexity and importance of balanced host-microbiota interactions.  Microbiome composition can be rapidly altered by exposure to antibiotics, with potential immediate effect on the health (acute diseases). For example a recent study of Ildiko et al. [1] showed that patients with UTI given an antibiotic were more likely to experience a subsequent UTI in the following weeks. However, antibiotics-induced changes of the gut microbiome can also indirectly affect health in long term (e.g. allergies/atopy/asthma) [2]. Once antibiotic treatment has stopped, the microbiome may present a certain degree of resilience, being capable of returning to a composition similar to the original one, but the initial state is often not totally recovered. In fact, antibiotic-induced microbiota alterations can remain after a long periods of time, spanning months and even years.

The question is whether GPs and patients take the biologic costs of antibiotic use into account sufficiently in making treatment decisions. Differences in perceptions about how risk-free antibiotic treatment is might in part account for the variation in rates of their use among GPs worldwide Evidence of alternative treatment strategies that could relieve symptoms and reduce antibiotic consumption is needed.

In patients who needed to be treated with antibiotics microbiome modulation to restore the human microbiome post antibiotic use might be a powerful strategy to improve resilience and health. Microbiota prevention- and intervention strategies, including complementary and alternative medicine (CAM), faecal transplant, prebiotics, probiotics and nutrition, might be effective strategies to conserve and steward the effects of antibiotics.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Lanfranco Fattorini photo

Lanfranco Fattorini

Istituto Superiore di Sanita, Italy

Title: Activity of antibiotics against dormant Mycobacterium tuberculosis

Biography:

Lanfranco Fattorini is responsible of the WHO Supranational Reference Laboratory of Rome for surveillance of drug-resistant TB, and is ECDC contact point for TB in Italy. In 2006 he set up the Wayne model of Mtb dormancy, and participated to the European FP6 project MILD-TB (Immunogenicity of Mtb lipids in the non replicating status of latency) and FP7 project STOPLATENT-TB (Latent tuberculosis: New tools for the detection and clearance of dormant Mtb). Presently, he is focussing the search of low-lipophilic drug containing combinations sterilizing dormant Mtb in hypoxia at pH 7.3, the pH of caseous granulomas, which is the hallmark of TB.

Abstract:

Statement of the problem: Tuberculosis (TB) is aninfectious disease caused by Mycobacterium tuberculosis(Mtb). Furthermore, about 2 billion people are latently infected with Mtb, with 10% of them reactivating to active disease. Antibiotic treatments require 6 months of combination therapy with isoniazid (INH)+rifampin (RIF)+pyrazinamide+ethambutol for active TB, and 9 months of INH or 3 months of rifapentine (RFP)+INH for latent TB. In the lungs of active and latent TB patients, cellular and caseous granulomas coexist, with Mtb ranging from aerobic actively replicating (AR) to anaerobic nonreplicating (NR), dormant, cells. Low oxygen pressure restricts growth of aerobic to anaerobic Mtb in cholesterol/triacylglycerolrich, low-vascularized, caseous granulomas, and allowing bacilli to transit into a dormant, drug-refractory, and state. In cellular granulomas, AR cells are killed by current therapy, while in caseous granulomas NR bacilli persist in a dormant state. New research approaches to eliminate NR Mtb surviving after therapy need to be developed, to shorten therapy of active TB below 6 months, and reduce the reservoir of latently infected individuals.

Methodology & Theoretical Orientation: Dormant cells were obtained by the Wayne model of hypoxia at pH 5.8 and 7.3 (mimicking cellular and caseous granulomas, respectively). AR and NR cells were treated with hydrophilic (logP≤0) and lipophilic (logP>0) drugs to find combinations sterilizing both cells, as determined by colony-counts and day-to-positivity (DTP >100 days) in MGIT960 system. Findings: At pH 5.8, lipophilic drugs were more active than hydrophilic agents against NR Mtb, and RIF+moxifloxacin+amikacin+pretomanid sterilized AR+NR cells after 14 days of exposure. At pH 7.3 (pH of caseum), out of 12 antibiotics tested, only RIF and RFP killed NR cells; the search for sterilizing low-lipophilic drug containing combinations is ongoing.

Conclusion and Significance: Overall, Wayne models can be useful for testing drug activity against dormant Mtb to guide the selection of future, shorter, rifamycin-containing therapies.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Yousif Mohammed Alfatih photo

Yousif Mohammed Alfatih

Sudan international University, Sudan

Title: Detection of a novel mutation G511T in the 530 loop in 16S rRNA in multi drugs resistant Mycobacterium tuberculosis isolated from Sudanese patients

Biography:

1-Yousif Mohammed Alfatih has completed his Bsc from University of science and Technology, Khartoum-Sudan, and Msc at the age of 25 years from, Sudan international University, Khartoum-Sudan.

3-Mohamed Ahmed Salih has completed his PhD in Molecular Genetics, from TUBINGEN UNIVERSITY, Institute of Human Genetics, Tubingen, German, and Postdoctoral Studies from HARVARD UNIVERSITY, Cambridge, MA. One Training fellowship Cancer Biology and Therapeutics Program (HMS-CBT), Harvard Medical School-USA.

 

Abstract:

Background:

 Tuberculosis (TB) is a bacterial disease considered as a global public health emergency by the World Health Organization (WHO) since 1993. In Sudan, MDR-TB represents a growing threat and one of the most important challenges that faced national tuberculosis program to establish a comprehensive multidrug-resistant tuberculosis management system.

Objective:

 To characterize the diversity and frequency of mutations in Sudanese MDR-TB strains isolated from Wad Madani, Al-Gadarif and Khartoum using 16S rRNA and phylogeny approach.

Material and Methods:

 A descriptive cross-sectional study was carry on total of 60 MDR-TB isolates from Wad-Madani, Al-Gadarif and Khartoum were tested with molecular LPA (Genotype MTBDR plus) and GeneXpert MTB/RIF assay and Spoligotyping to confirm their resistance to RIF and INH. Sequencing and phylogenetic analysis was carried out using in silico tools.

Result:

 This study revealed the circulation of different Sudanese MDR-TB strains isolated from Wad Madani and Al-Gadarif belonging to two distinct common ancestors. Two isolates from Wad Madani (isolate3 and isolate11) found in one main group which characterized by a novel mutation G511T in the 530 loop.

Conclusion:

 The recurrence of C217A mutation in Al-Gadarif (isolate11) indicates the spread of this mutation in Sudanese MDR-TB strains and the diversity of this inheritance leading to generate new G511T novel mutation. So, understanding the molecular characterization of resistance mechanisms in MD-TB can facilitate the early detection of resistance, the choice of appropriate treatment and ultimately the management of MD-TB transmission. Bioinformatics approaches provide helpful tools for analyzing molecular mechanisms of resistance in pathogens.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Ahmad Hussen Tareq photo

Ahmad Hussen Tareq

Nanyang Technological University, Singapore

Title: Amide derivatives of vancomycin to overcome antibiotics resistance

Biography:

Dr. Ahmad Hussen Tareq has expertise in developing peptide based antibacterial agents to overcome antibiotic resistance. He focused on synthesis and modification of potent glycopeptide antibiotics like vancomycin and teixobactin to overcome bacterial drug resistance. He worked on the diverse chain of antibiotic drug development, from lead discovery, drug development, chemical modification, In vivo/In vitro testing, pharmacological analysis to pre-clinical trials. In the above mentioned projects, he utilized carboxamide bond formation to develop simple and highly efficient methodology for vancomycin analog synthesis. As extension of his work, he developed method for synthesis of Teixobactin analogs. These next generation antibiotics can significantly help in our fight against bacterial drug resistance.

Abstract:

Glycopeptide antibiotics were once considered as drug of choice of serious gram positive infections. These antibiotics interrupt bacterial cell wall synthesis to exert their antibacterial effects. They pose higher barrier for drug resistance development, as they target non-protein components of bacterial cell wall. However, these antibiotics are increasingly becoming less effective due to emergence of resistant strains. To address this issue, modification of glycopeptide antibiotics to enhance their activity is therefore a useful strategy to develop new compounds against drugresistant strains. We explored an underutilized reactive site on the glycopeptide antibiotics and developed a simple yet highly efficient scheme to synthesize various analogs. Using this scheme, the C-terminal carboxyl group of vancomycin was reacted with amine compounds to yield carboxamide analogs some of which with improved antibacterial activity upto 100 times. Usually multiple chemical reactions are needed to prepare antibiotic analogs. Our single-step scheme provides a simple yet efficient methodology to develop potent analogs of vancomycin. Different analogs are synthesized by reacting series of diamines with vancomycin.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Lucia Santos photo

Lucia Santos

University of Coimbra, Portugal

Title: Antimicrobial use in aquaculture: Patterns and current knowledge on its contribution to the emergence and spread of antimicrobial resistance

Biography:

Lúcia Santos is a pharmacist, Master in Public Health, presently perusing her PhD degree in Food Security in Coimbra University – Portugal. Her investigation work has been focusing on food security, essentially related to the presence of antimicrobial residues in fish and related consequences on public health. Special focus is being given on the impact of antibiotic use in aquaculture on the global health crisis of antimicrobial resistance.

Abstract:

Aquaculture is a fast-growing industry accounting nowadays for almost half of the fish supplies for human consumption, worldwide. The intensive and semiintensive practices used to produce large stocks of fish, in small spaces, originate frequent disease outbreaks and, to control it, the use of antimicrobials, for prophylactic and therapeutic purposes, is a customary practice. The selective pressure exerted by these drugs – usually present in sub-therapeutic doses for prolonged periods, in water and sediments – represent the ideal framework for the emergence and selection of resistant bacterial strains, promoting and stimulating horizontal gene transfer. Passage of antimicrobial resistant genes and antimicrobial-resistant bacteria from aquatic to terrestrial animal husbandry and to human environments, and vice versa, with detrimental effects on both human and animal health, and also in aquatic ecosystem, is now largely recognized. A global effort must be developed in order to cease antimicrobial overuse in aquaculture, encouraging stakeholders to adopt other disease preventive measures, such as adequate hygiene standards, vaccines or probiotics, among others. Shaping a new path is crucial, in order to contain the increasing threat of antimicrobial resistance. Being antimicrobial resistance a global ecological event, the One Health strategy is the most appropriate way to address and tackle it. As postulated by One Health principle we must recognize that human, animal and environmental health are interconnected, that diseases are transmitted from humans to animals, and vice versa, and must therefore be tackled in both.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Ester Boix photo

Ester Boix

Universitat Autonoma De Barcelona, Spain

Title: Human ribonucleases and derived peptides to tackle antimicrobial resistance

Biography:

Ester Boix is leading the research group on “Human host defence RNases” at the Universitat Autonoma de Barcelona, Spain. She was awarded in 2002 as a Ramon y Cajal senior researcher and is Full Professorship accredited since 2016. She has published more than 70 papers in peer-review journals, mostly as a corresponding author. Her main research interests are focus on the mechanism of action of human antimicrobial RNases, as promising proteins for drug design. Her research group is pioneer in the development of expression protocols for recombinant RNases, first report of human RNases structural studies by X-ray crystallography and identification of RNases host defence properties. Latest works are based on structural- functional studies of antimicrobial RNases towards the identification of functional domains applied to the design of novel antibiotic agents to combat bacterial resistance.

Abstract:

Emergence of bacterial resistance to most common antibiotics urges the design of novel antimicrobial drugs. Antimicrobial proteins andpeptides (AMPPs) are key players of the host innate immunity and exert a rapid and multifaceted action that reduces the development of bacterial adaptation mechanisms. Our research group has been long-time exploring the mechanism of action of human ribonucleases involved in host defence. Human host defence RNases are members of the vertebrate specific RNase A superfamily. They are expressed by a diversity of innate immune cells and are endowed with antimicrobial properties. Secreted upon infection, they contribute to protect our body fluids from invading pathogens. We have identified the structural determinants that determine the protein antimicrobial activity. A combined multifaceted action ensures an efficient eradication of bacterial resistant forms such as biofilm communities and macrophage intracellular resident Mycobacteria. Based on structurefunctional studies and by applying a positional scanning library we have identified the minimal pharmacophore entity and designed derived peptides that encompasses most of the parental protein properties. The results underline the potentiality of RNases and derivatives as alternative antibiotics to combat bacterial resistance.
Funding: Ministerio de Economía y Competitividad (SAF2015- 66007P) and Agència de Gestió d’Ajuts Universitaris i de Recerca, Programa Indústria del coneixement (2016 PROD- 00060), co-financed by FEDER funds.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Seiji Negoro photo

Seiji Negoro

University of Hyogo, Japan

Title: Protein stability and subunit assembly of nylon hydrolase: Structural basis discriminating correct subunit assembly, aggregation, and intracellular degradation of precursor protein

Biography:

Seiji Negoro is the Professor at the Department of Applied Chemistry, Graduate School of Engineering, University of Hyogo. He has completed PhD from Graduate School of Engineering, Osaka University, Japan in 1982. He appointed as Research associate at the Department of Biotechnology, Osaka University from 1982-1992. He served as an Associate professor at the Department of Biotechnology, Osaka University from 1992-1997. His Scientific research field focuses on Enzymology, Protein engineering, Environmental biotechnology.

Abstract:

Protein-protein interactions leading to correct subunit assembly play important roles in protein stability and/ or various biological functions, which could include thefollowing: i) regulation of enzyme activities by the allosteric effect, ii) generation of an active center by utilizing several catalytic/substrate-binding residues located in different subunits, and iii) generation of a multifunctional enzyme by integrating several functions initially compartmentalized in different enzyme subunits into a single oligomeric enzyme. In addition, the stability of a monomeric protein is generally improved by the oligomerization of the protein. Nylon hydrolase (NylC) is one of the three enzymes (NylABC) responsible for the degradation of the by-products of nylon-6 manufacture (cyclic and linear oligomers of 6-aminohexanoate (Ahx) with a degree of polymerization greater than three) and various aliphatic nylons (nylon-6, nylon-66, etc.) (Fig. 1) (1-8). NylC is initially expressed as an inactive precursor (36 kDa). However, the precursor is cleaved auto-catalytically at Asn266/Thr267 to generate an active enzyme composed of α (27 kDa) and β (9 kDa) subunits. Four αβ heterodimers (molecules A-D) form a doughnut-shaped quaternary structure (Fig. 2). In this study, the thermostability of the parental NylC was altered by amino acid substitutions located at the A/D interface (D122G/H130Y/D36A/L137A) or the A/B interface (E263Q) and spanned a range of 47 °C (5,6). From the analytical centrifugation data of the various mutant enzymes, we conclude that the assembly of the monomeric units is dynamically altered by the mutations. Considering structural, biophysical, and biochemical analyses, we discuss the structural basis of the stability of nylon hydrolase. Finally, we propose a model that can predict whether the fate of the nascent polypeptide will be correct subunit assembly, inappropriate protein-protein interactions causing aggregation, or intracellular degradation of the polypeptide.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Mandira Varma-Basil photo

Mandira Varma-Basil

University of Delhi, India

Title: Role of efflux pumps in drug resistance in M. tuberculosis

Biography:

Prof. Mandira Varma Basil is a Medical Microbiologist currently working at Vallabhbhai Patel chest Institute, Delhi, India where she is incharge of the Mycobacteriology unit. She obtained her MD in Microbiology from the University of Delhi and her DNB from the National Board of Examinations, Delhi, India. She is the recipient of the Department of Biotechnology (Government of India) Overseas Associateship and the Indian Council of Medical Research International Fellowship. Her main areas of interest include TB diagnosis, drug resistance in M. tuberculosis, molecular epidemiology of M. tuberculosis and non-Mycobacteria tuberculous. Dr. Varma-Basil has several publications and book chapters to her credit.

Abstract:

Genomic mutations in drug targets have been identified as the major cause of drug resistance in M. tuberculosis. However, a section of isolates do not possess these mutations despite being drug resistant. Approximately 20 to 30% of clinical isoniazid (INH) resistant, 5% rifampicin (RIF) resistant and 40% Ethambutol (EMB) resistant M. tuberculosis isolates do not harbor mutations. Therefore, it is evident that other, more undefined mechanisms play a role in drug resistance. Analysis of genome sequences has shown that M. tuberculosis have multiple putative efflux pumps. However, the role of efflux pumps in intrinsic and acquired resistance has been neglected as a major cause for antibiotic resistance of M. tuberculosis and has only recently received attention. We evaluated the role of putative efflux pumps in providing esistance to INH, RIF and EMB in clinical isolates of M. tuberculosis. Isolates were also analysed for canonical mutations in katG, inhA, rpoB and embB306. Our study suggested a possible association of efflux pumps and resistance to RIF, INH and EMB. Although the mechanism behind efflux pumps overexpression and regulation is notclearly understood, it could be relevant to study mutations upstream or in the predicted promoter region of these genes to identify additional molecular markers for drug resistance.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Sanjib Bhakta photo

Sanjib Bhakta

University of London, UK

Title: The pain-killer carprofen elicits pleiotropic mechanisms of bactericidal action with potential to reverse antimicrobial drug resistance in tuberculosis

Biography:

Sanjib Bhakta is a reader in Molecular Microbiology and Director of Mycobacteria Research Lab at ISMB, Birkbeck, University of London & UCL. His specialties are : Microbiology, Molecular Biology & Biochemistry, Drug Discovery, Target Identification and validation in Mycobacterium tuberculosis, Model & Method development (in vitro & ex vivo) for whole cell (phenotypic) screening of inhibitors, drug susceptibility testing, repurposing drugs.

Abstract:

The alarming rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated tuberculosis (TB) control to a major global health challenge. Repurposing drugs with known clinical properties and safety profiles offers a direct route to clinical trials. Our earlier studies using a whole-cell, high throughput phenotypic assay (HT-SPOTi) revealed that carpofen, a non-steroidal anti-inflammatory drug (NSAID), selectively inhibited the growth of replicating, non-replicating and multi-drug-resistant clinical isolates of M. tuberculosis [1-6]. The antibacterial activity of NSAIDs has been confirmed independently as in the case of aspirin and ibuprofen reducing mycobacterial loads in murine models. NSAIDs have also demonstrated sensitisation of mycobacteria to other antimicrobials. We have investigated the mechanisms through which NSAIDs eliminate M. tuberculosis from the host environment. Integrative molecular and microbiological approaches showed that carprofen, a bactericidal drug, inhibited bacterial drug efflux mechanisms. Carprofen also restricted mycobacterial biofilm-like growth, highlighting the requirement of effluxmediated communicative systems for the formation of biofilms. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential, which may explain why spontaneous drug-resistant mutants could not be isolated in practice due to the pleiotropic nature of carprofen’s anti-tubercular action. This repurposed mycobactericidal and immunomodulatory drug has the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations.

Meetings International - Antibiotics-2020 Conference Keynote Speaker Giulio Tarro photo

Giulio Tarro

Foundation de Beaumont Bonelli for cancer research, Italy

Title: Tumor liberated protein (TLP) as potential vaccine for lung cancer patients

Biography:

Giulio Tarro graduated from Medicine School, Naples University in 1962. He worked as Research Associate at Division of Virology and Cancer Research, Children’s Hospital from 1965-1968, and Assistant Professor of Research Pediatrics College Medicine from 1968-1969, Cincinnati University, Ohio. Oncological Virology. He has been the Professor at Naples University from 1972-1985, the Chief Division Virology from 1973-2003, the Head Department Diagnostic Laboratories from 2003-2006. Since 2007 he has been the Chairman Committee of Biotechnologies and Virus Sphere, World Academy Biomedical Technologies, UNESCO, the Adjunct Professor Department Biology, Temple University, College of Science and Technology, Philadelphia and the recipient of the Sbarro Health Research Organization lifetime achievement award (2010). His researches have been concerned with the characterization of specific virus-induced tumour antigens, which were the "finger-prints" left behind in human cancer. Achievements include patents in field; discovery of Respiratory Syncytial Virus in infant deaths in Naples and of tumor liberated protein as a tumor associated antigen, 55 kilodalton protein overexpressed in lung tumors and other epithelial adenocarcinomas.

Abstract:

Previous studies have investigated the potential role of blood-based tumor markers for early detection, diagnosis, prognostication, post-operative follow- p as well as monitoring of tumor burden and response to treatment in advanced disease stages. To date, the most commonly used markers include neuron specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1) and cancer antigen CA 125 (CA 125). However, low sensitivity, specificity or reproducibility limit their clinical utility in the care of patients with lung cancer and no single marker has gained widespread acceptance as diagnostic test, prognostic indicator or monitor of treatment response. Ideally, a tumor marker should have a sensitivity and specificity of 100%, a goal that is almost never achieved. In 1983, a tumor-associated antigen was isolated from NSCLC and named tumor liberated protein (TLP). The immunohistochemical analysis revealed a cytoplasmic localization of TLP in small and larger granules. In some specimens it was also detected in the lumen of atypical glands and in the bronchial secretions, suggesting that TLP could be considered a secretory product of neoplastic cells. Tarro et al. have demonstrated that when TLP is extracted from a patient’s tumor, purified in the laboratory and reintroduced into the body, it boosts an immune response in the host. The partial sequence analysis of this protein led to the synthesis of corresponding antigenic peptides that have been used to produce antisera in rabbits. According to Tarro et al., four TLP-derived peptides were identified: RTNKEASI, GSAXFTN, QRNRD and GPPEVQNAN. Anti- RTNKEASI rabbit sera reacted specifically with NSCLC tumor extracts as well as sera from lung cancer patients. TLP was detected in sera of 53.1% of NSCLC patients (N = 534) with 75% being positive in the early stage (stage I) dropping to 45% in the late stage (stage IV), suggesting a potential role as early screening biomarker.