This session will be broken down into 2 parts.

From 10-10.30 Gill Douce will offer an introduction to the option

From 10.30 Lorena Fernandez-Martinez will discuss the global impact of antimicrobial resistance

Session Outline: Antibiotic resistance – a global threat

Antibiotic resistance is one of the top global public health and
development threats. It is estimated that antibiotic resistance was responsible for 6.22 million global deaths in 2019. Priorities to address antibiotic resistance in human health include preventing infections; ensuring access to accurate diagnosis and appropriate treatment of infections; antibiotic use surveillance, and research and development for novel vaccines, diagnostics and antibiotics. This session introduces the complex issue of antibiotic resistance, the current challenges facing novel antibiotic discovery, and current research at UoG to
find new and effective antibiotics.

Intended learning outcomes:
At the end of this session, you should be able to:
-         Understand the complexity of the antibiotic resistance problem
-         Understand the challenges facing antibiotic discovery
-          Discuss strategies to combat antibiotic resistance
 
Key References:

1. World Health Organization
Antimicrobial resistance fact sheet: https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance 
Global antimicrobial resistance and use surveillance system (‎GLASS)‎ report 2022: https://www.who.int/publications/i/item/9789240062702 

2. Antimicrobial Resistance Collaborators. (2022). Global burden
of bacterial antimicrobial resistance in 2019: a systematic analysis. The
Lancet; 399(10325): P629-655. DOI: 10.1016/S0140-6736(21)02724-0

3. Drug-Resistant Infections: A Threat to Our Economic future
(March 2017) https://www.worldbank.org/en/topic/health/publication/drug-resistant-infections-a-threat-to-our-economic-future

4. Walesch, S., Birkelbach, J., Jézéquel, G., Haeckl, F.J., Hegemann, J.D., Hesterkamp, T.,Hirsch, A.K., Hammann, P. and Müller, R., 2023. Fighting antibiotic resistance—strategies and (pre) clinical developments to find new antibacterials. EMBO reports, 24(1), p.e56033. DOI: 10.15252/embr.202256033

Mycobacteria – a global threat

 There are over 180 mycobacterium species, including the notorious Mycobacterium tuberculosis that causes tuberculosis and the ‘biblical’ Mycobacterium leprae that causes leprosy. Tuberculosis is a preventable and curable disease, but over a million people die from it every year, and leprosy still affects millions worldwide. Why are tuberculosis and leprosy not eradicated? This session covers the biology of pathogenic mycobacteria and their pathogenesis, the prevention and treatment strategies, and the current challenges of emerging non-tuberculous mycobacterial infections caused by environmental mycobacteria found in water and soil.

Intended learning outcomes:

At the end of this session, you should be able to:

-          Provide examples of diseases caused by mycobacteria

-          Discuss prevention and treatment for mycobacterial infections

-          Evaluate strategies to combat the emerging mycobacterial infections

 

Key References

1. World Health Organization

Tuberculosis fact sheet: https://www.who.int/news-room/fact-sheets/detail/tuberculosis

Leprosy fact Sheet: https://www.who.int/news-room/fact-sheets/detail/leprosy

2. Ahmad Zaheen and Barry R. Bloom. Tuberculosis in 2020 - New Approaches to a Continuing Global Health Crisis (Interaction Perspective), The New England Journal of Medicine, 2020, DOI: 10.1056/NEJMp2000325.

3. Steven Cowman, Jakko van Ingen, David E. Griffith, Michael R. Loebinger. Non-tuberculous mycobacterial pulmonary disease, European Respiratory Journal 2019, DOI: 10.1183/13993003.00250-2019.

4. Cara M. Gill, Lorraine Dolan, Laura M. Piggott, Anne Marie McLaughlin. New developments in tuberculosis diagnosis and treatment, Breathe 2022, DOI: 10.1183/20734735.0149-2021.

Paper analysis

Cody R. Ruhl, Breanna L. Pasko, Haaris S. Khan, Lexy M. Kindt, Chelsea E. Stamm, Luis H. Franco, Connie C. Hsia, Min Zhou, Colton R. Davis, Tian Qin, Laurent Gautron, Michael D. Burton, Galo L. Mejia,4,5 Dhananjay K. Naik, Gregory Dussor, Theodore J. Price, and Michael U. Shiloh. Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough, Cell 2020, DOI: 10.1016/j.cell.2020.02.026.

 

Dr Leighann Sherry

Synopsis

Until relatively recently the common perception within the field of microbiology has been that of individual bacteria existing as a planktonic unicellular form that are able to replicate within the host and using their armamentarium of virulence factors induce pathological changes and disease. This remains the likeliest scenario for most acute infections, which appear rapidly and cause an intense host inflammatory response. This type of infection tends to respond to antibiotic therapy augmented by the host response, as the microorganisms present are usually in a planktonic state. However, for chronic infection the sequence of events associated with the disease process is likely to be different due to the presence of biofilm. This component will investigate the clinical relevance of microbial biofilms, the role of polymicrobiality in disease, and explore the primary reasons for their importance with reference to antimicrobial resistance. Key antimicrobial resistance mechanisms will be explored and novel methods biofilm use to outwit the host.

Aims:

To understand to importance and clinical relevance of microbial biofilms

To understand and provide key examples of biofilm resistance mechanisms

To understand the importance of the microbiome and mixed species biofilm infections

To critically discuss the importance of clinical biofilm infections and how we can use our understanding of them for their diagnosis

References

Ramage G et al 2010. Are we any closer to beating the biofilm: novel methods of biofilm control. Curr Opin Infect Dis. Dec;23(6):560-6

Koo et al. 2017. Targeting microbial biofilms: current and prospective therapeutic strategies. Nat Rev Microbiol. 15(12):740-755.

O’Donnell et al. 2015. Polymicrobial Candida biofilms: friends and foe in the oral cavity. FEMA Microbiology Letters. 15(7.)

Synopsis

In recent decades, most pathogens have become progressively more contagious, more virulent and more resistant to antibiotics. This implies a rather dynamic evolutionary capability, representing a remarkable level of genomic plasticity, most probably maintained by horizontal gene transfer (HGT) but also by changes affecting the bacterial “core” genome. In this lecture we will discuss recent developments in the understanding of how pathogenic bacteria can evolve from non-pathogenic strains by acquisition of virulence genes. Understanding the genetic and ecological factors which support the emergence of new clones of pathogenic bacteria is vital to develop preventive measures.

Aims:

At the end of this session, you should be able to:

Provide specific examples of different strategies involved in the emergence and spread on novel virulent clones

Discuss how the different antibiotic treatments can help/drive this process

Evaluate how future strategies might be used to counteract these strategies

References

Deurenberg, R.H., and Stobberingh, E.E. (2008) The evolution of Staphylococcus aureus. Infect Genet Evol 8: 747–763

Faruque, S.M., and Mekalanos, J.J. (2012) Phage-bacterial interactions in the evolution of toxigenic Vibrio cholerae. Virulence 3: 556–565

Mandel, M.J., Wollenberg, M.S., Stabb, E.V., Visick, K.L., and Ruby, E.G. (2009) A single regulatory gene is sufficient to alter bacterial host range. Nature 458: 215–218

Rasko, D. A. et al. (2011) Origins of the Escherichia coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. N. Engl. J. Med. 365, 709–717

Professor Mark Roberts

Synopsis

Within and outside of their hosts bacterial pathogens such as Salmonella sp. and E. coli encounter environments and agents deleterious to their growth and survival. Consequently Salmonella, E. coli and other microorganism possess highly efficient systems that allow them adapt to these environments, detoxify or nullify the action of the toxic agents and repair or remove damaged cellular components. These are collectively called stress responses. Some of these stress responses are absolutely essential for pathogens to causes infections. Appropriate activation and deactivation of the different stress response systems is necessary for bacterial success. We will discuss the most important stress response systems of pathogenic salmonella and E. coli strains. Their function, regulation, interaction and role in pathogenesis will be described.

Aims

At the end of this session, you should be able to:

Describe the important stress response systems of pathogenic salmonella and E. coli;

Describe the regulation of these stress responses, the genes they regulate and their function;

Detail how the different stress responses interact.

References

Rowley, G., M. Spector, J. Kormanec, and M. Roberts. 2006. Pushing the envelope: extracytoplasmic stress responses in bacterial pathogens. Nat Rev Micro 4:383-394.

Dong T1, Schellhorn HE. 2010. Role of RpoS in virulence of pathogens. Infect Immun. 78:887-97.

Rowley, G., Skovierova, H., Stevenson, A., Rezuchova, B., Homerova, D., Lewis, C., Sherry, A., Kormanec, J., and Roberts, M. (2011). The periplasmic chaperone Skp is required for Salmonella Typhimurium infection in a murine Typhoid model. Microbiology. 157, 848-858.

Humphreys,S., Rowley,G., Stevenson,A., Anjum,M.F., Woodward,M.J., Gilbert,S., Kormanec,J., and Roberts,M. (2004): Role of the two-component regulator CpxAR in the virulence of Salmonella enterica serotype Typhimurium. Infect Immun, 72:4654-4661.

Battesti A, Majdalani N, Gottesman S. 2011. The RpoS-mediated general stress response in Escherichia coli. Annu Rev Microbiol. 65:189-213.

Roberts, M., Rowley, G., Kormanec, J., and Zalm, M. 2017. The Role of Alternative Sigma Factors in Pathogen Virulence. pp 229 – 303. In: “Foodborne Pathogens: Virulence Factors and Host Susceptibility” Ed Gurtler, J. et al.   Springer International Publishing.

Antimicrobial Resistance and Designing Novel Antibiotics

Laura McCaughey Synopsis

Antibiotic resistance is one of the biggest public health challenges of our time. Resistance developing to currently used antibiotics combined with a lack of new antibiotics in the development pipeline has led to alternatives to antibiotics being sought. This is particularly true for Gram-negative bacteria, for which no new antibiotic classes have been approved for human use since 1987. There are currently many alternative approaches to treating bacterial infections in different stages of research, development and approval. This lecture will explore some of these alternatives, and some novel small molecule antibiotics, and look at the advantages and disadvantages of them along with their mechanisms of action.

Part 1 (Pre-recorded lecture). In this lecture we will briefly recap the problem of antibiotic resistance and the barriers to developing antibiotics against Gram-negative bacteria. The rest of this lecture will focus on targets in the outer membrane of Gram-negative bacteria with therapeutic potential.

Part 2. Please read in advance parts of review 1 - ‘Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance’ and parts of review 2 – ‘Narrow-spectrum antibacterial agents’. The important sections to read are detailed in the pre-recorded session.

In an interactive live session we will discuss the varied approaches to alternative antibiotic therapies before discussing the advantages, disadvantages, limitations and barriers of using broad spectrum and narrow spectrum antibiotics. Content from the reviews will be examinable.

Reviews:

Ghosh C, Sarkar P, Issa R, Haldar J. Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance. Trends Microbiol. 2019 Apr;27(4):323-338. doi: 10.1016/j.tim.2018.12.010.

Melander R, Zurawski D, Melander C. Narrow-spectrum antibacterial agents. Med Chem Comm. 2018 Jan;9(1):12-21. Doi: 10.1039/c7md00528h

Aim

To describe alternatives to antibiotics in the context of antibiotic resistance

 Intended Learning Outcomes

To outline the multiple components of the problem of antibiotic resistance

To relate the problem of antibiotic resistance with the need for alternatives to antibiotics

To compare and contrast broad spectrum and narrow spectrum antibiotics

To determine if therapeutics are broad spectrum or narrow spectrum

To categorise a range of alternatives to antibiotics and expand on each category with specific examples

To explore how different types of therapeutics can work on the same target

Extra reading

Ghequire MGK, Swings T, Michiels J, Buchanan SK, De Mot R. 2018. Hitting with a BAM: selective killing by lectin-like bacteriocins. mBio 9:e02138-17. https://doi.org/10.1128/mBio.02138-17.

Hart EM, Mitchell AM, Konovalova A, Grabowicz M, Sheng J, Han X, Rodriguez-Rivera FP, Schwaid AG, Malinverni JC, Balibar CJ, Bodea S, Si Q, Wang H, Homsher MF, Painter RE, Ogawa AK, Sutterlin H, Roemer T, Black TA, Rothman DM, Walker SS, Silhavy TJ. A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier. Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21748-21757. doi: 10.1073/pnas.1912345116.

Storek KM, Auerbach MR, Shi H, Garcia NK, Sun D, Nickerson NN, Vij R, Lin Z, Chiang N, Schneider K, Wecksler AT, Skippington E, Nakamura G, Seshasayee D, Koerber JT, Payandeh J, Smith PA, Rutherford ST. Monoclonal antibody targeting the β-barrel assembly machine of Escherichia coli is bactericidal. Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):3692-3697. doi: 10.1073/pnas.1800043115.

Li Y, Zhu X, Zhang J, Lin Y, You X, Chen M, Wang Y, Zhu N and Si S (2020) Identification of a Compound That Inhibits the Growth of Gram-Negative Bacteria by Blocking BamA–BamD Interaction. Front. Microbiol. 11:1252. doi: 10.3389/fmicb.2020.01252

Imai, Y., Meyer, K.J., Iinishi, A. et al. A new antibiotic selectively kills Gram-negative pathogens. Nature 576, 459–464 (2019). https://doi.org/10.1038/s41586-019-1791-1

Urfer M, Bogdanovic J, Lo Monte F, Moehle K, Zerbe K, Omasits U, Ahrens CH, Pessi G, Eberl L, Robinson JA. A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli. J Biol Chem. 2016 Jan 22;291(4):1921-1932. doi: 10.1074/jbc.M115.691725.

Prof Matthew Holden (University of St Andrews)

Synopsis

Matthew is Professor of Bacterial Genomics in the School at Medicine at the University of St Andrews, and has an honorary consultancy with NHS National Services Scotland. He started his career with a BSc (Hons) in Biochemistry from the University of St Andrews, and then completed a PhD in Molecular Microbiology at the University of Warwick. Prior to moving to the University of St Andrews, Matthew spent 13 years at the Wellcome Trust Sanger Institute working in the Pathogen genomics group. During his time there he annotated and analysed a range of diverse genomes, from Yersinia pestis, the causative agent of the plague, through to algal viruses. In recent years he has spent much of his time focused on Staphylococcus aureus, using whole genome sequencing to study the genetics and evolution of this versatile opportunistic pathogen.

Since moving to St Andrews two and half years ago, Matthew has established a research group focusing on experimental and translational genomics, and is a genomics lead in the Scottish Healthcare Associated Infections Prevention Institute (SHAIPI) consortium. His research interests include: the survival and evolution of methicillin-resistant S. aureus (MRSA), the genetic basis of antibiotic resistance, and the application of whole genome sequencing (WGS) in a clinical setting to combat hospital-associated infections.

This session will focus on how WGS can be used to investigate the genetic diversity of pathogen populations and their evolution, and how also how WGS can be used to investigate the transmission of bacterial pathogens in healthcare settings. Matthew will describe his research into the emergence and spread of MRSA, and effect that the widespread use of antimicrobials has had in shaping the pathogen population. He will also describe example of how WGS had been used to identify outbreaks, and some of the some of the considerations for the use and interpretation of data from this powerful forensic tool. As part of the session Matthew will explore the potential can of worms that can be opened up when WGS is used identify the source of transmissions.

Aims:

Describe the organisation and structure of the Staphylococcus aureus genome and understand the mechanism that shape it

Discuss the factors that contribute to the emergence of epidemic clones

Appraise of the advantages and limitations of using WGS to investigate outbreaks

References

Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol. 2009 Sep;7(9):629-41. doi: 10.1038/nrmicro2200. Review. PubMed PMID: 19680247; PubMed Central PMCID: PMC2871281.

Fitzgerald JR, Holden MT. Genomics of Natural Populations of Staphylococcus aureus. Annu Rev Microbiol. 2016 Sep 8;70:459-78. doi: 10.1146/annurev-micro-102215-095547. PubMed PMID: 27482738.

Aanensen DM, et al., Whole-Genome Sequencing for Routine Pathogen Surveillance in Public Health: a Population Snapshot of Invasive Staphylococcus aureus in Europe. MBio. 2016 May 5;7(3). pii: e00444-16. doi: 10.1128/mBio.00444-16. PubMed PMID: 27150362; PubMed Central PMCID: PMC4959656.

Croucher NJ, Didelot X. The application of genomics to tracing bacterial pathogen transmission. Curr Opin Microbiol. 2015 Feb;23:62-7. doi: 10.1016/j.mib.2014.11.004. Review. PubMed PMID: 25461574.

Dr Gill Douce and Dr Dónal Wall

Synopsis

Our knowledge regarding the organisms that reside and proliferate within different environmental niches has massively increased in the last ten years as a consequence of our capacity to sequence and analyse metagenomic data sets. In many cases, this analysis has led to the identification of new species of organisms that proved refractory to culture in the laboratory. The application of novel methodologies to understand the metabolites being released from the microbiome is also providing insights into communication between the microbiome and us, identifying mechanisms by which the microbiome can impact human health. Study of the ‘microbiome’ from different sites on the human body offers new insights into the role of many of these microbes in maintaining the body in a ‘healthy’ state. Within this session, we will discuss the major developments in this area including the methods used in analysis, evidence offered in support of these associations and the therapeutic opportunities such knowledge offers. We will showcase examples of how the microbiome has been implicated or plays a defined role in diseases such as diabetes, inflammatory bowel disease and multiple sclerosis.

Aims

To describe the methods used in the evaluation and analysis of microbiome data

To explain the role played by the microbiota in maintenance of the healthy gut

To compare and contrast the microbiome changes observed in the diseased gut

To examine the opportunities for modification of microbiome content

References

Owyang, C., Wu. G. D. The Gut Microbiome in Health and Disease. Gastroenterology, Volume 146, 2014, Pages 1433–1436

Neish, A. S. Microbes in Gastrointestinal Health and Disease Gastroenterology, Volume 136, 2009, Pages 65–80

Garrett, W. S. , Gordon, J. I., Glimcher, L. H. Homeostasis and Inflammation in the Intestine. Cell, Volume 140, 2010, Pages 859–870

Doré J, Blottière H. The influence of diet on the gut microbiota and its consequences for health. Curr Opin Biotechnol. 2015;32C:195-199

McLean MH, Dieguez D Jr, Miller LM, Young HA. Does the microbiota play a role in the pathogenesis of autoimmune diseases? Gut. 2015;64(2):332-341

Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014 12(10):661-72

Dr Jeannine Hautvast (Radboud university medical center – Nijmegen, the Netherlands) and Dr Gill Douce

Vaccine hesitancy is a complex issue, which global vaccination as a consequence of the COVID pandemic, has helped develop into a major topic for discussion for the general public.  In this session, we will discuss the historical development of hesitancy and the factors associated with its development, the different beliefs that underpin unwillingness to be vaccinated and the consequences of the behaviour of vaccine hesitancy in the context of infectious diseases outwith COVID.

Jeannine is a Physician working in Public Health at the Regional Public Health Service of "GGD Gelderland-Zuid" and at the department of Primary and Community care of the Radboudumc, Nijmegen. She is involved in public health practice of infectious diseases control; has a research interest in the field of vaccine acceptance, zoonoses, impact of infectious diseases, and STI.  She also teaches medical and biomedical undergraduates .

Aims:

1.     To discuss the complex issue of vaccine hesitancy (VH) and its global impact on the prevention of disease generally.

2.     To understand the concept of vaccine hesitancy, its history and the characteristics of the VH key groups and the factors playing a role in the occurrence of VH

3.     To highlight the evidence-based practices to address VH groups and the pro’s and con’s of mandatory vaccination. 

 References:

Hadjipanayis A, Esso van D, Torso del A, et al. Vaccine confidence among parents: large scale study in eighteen European countries. Vaccine 2020; 38(6): 1505-12 (doi: 10.1016/j.vaccine.2019.11.068).

Fournet N, Mollema L, Ruijs WL, et al. Under-vaccinated groups in Europe and their beliefs, attitudes and reasons for non-vaccination; two systematic reviews.  BMC Public Health 2018; 18: 196 (DOI: 10.1186/s12889-018-5103-8 )

Cataldi JR, O’Leary ST. Parental vaccine hesitancy: scope, causes, and potential responses. Curr Opin Infect Dis 2021; 34(5): 519-26 (doi: 10.1097/QCO.0000000000000774.)

Dr Gill Douce 

Synopsis

With the development of high throughput screening and genomic analysis, we are in a stronger position than ever to develop new and more effective vaccines. Within this session, we will evaluate the implications of applying these technologies to antigen identification and vaccine design. This will include discussion of new routes of delivery and the effect that modification of an adjuvant may play on the immune response generated.

Aims:

To appraise the impact of ‘omic’ technologies in the identification and development of new vaccine candidates

To understand the potential offered by novel routes of immunisation on the size and quality of the immune response generated

To discuss the ethical implications of the cost and testing of new vaccines in countries with developed and developing economies

To discuss the impact of vaccine hestiency on gobal rollout of vaccines

References

Seib KL, Zhao X, Rappuoli R. Developing vaccines in the era of genomics: a decade of reverse vaccinology. Clin Microbiol Infect. 2012 Suppl 5:109-16

Unnikrishnan M, Rappuoli R, Serruto D. Recombinant bacterial vaccines. Curr Opin Immunol. 2012 24(3):337-42

Mohan T, Verma P, Rao DN. Novel adjuvants & delivery vehicles for vaccines development: a road ahead. Indian J Med Res. 2013 138(5):779-95

Brito LA, O'Hagan DT. Designing and building the next generation of improved vaccine adjuvants. J Control Release. 2014 190:563-79