Antibacterial Drug Discovery

Why is antimicrobial resistance a threat?

If we don't act now, anyone could be in hospital for a long period of time for minor surgery and die due to an ordinary infection that can't be treated by antibiotics. Things as common as Strep Throat or a child's scratched knee could kill once again

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Describe the trends in crude mortality rates for all causes (non-infectious causes and infectious diseases) over the period 1900-1996

General decrease in mortality rate over time. General decrease in infectious diseases, general increase in non-infectious causes. Sharp peak around 1914-18 (First World War). Infectious diseases trend expected to increase again

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State features of global antimicrobial resistance threats (1)

Antimicrobial resistance is no longer a third world problem. Pharmaceutical companies cannot make profit from producing new antibiotics. By 2020, prediction of 10 million people to die from antimicrobial resistance

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State features of global antimicrobial resistance threats (2)

More of a threat than cancer (cancer treatment could prolong life by a few years, MRSA infection - short duration of life (days))

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What is the impact of AMR on the world economy?

$20 billion in excess direct healthcare costs with additional costs to society for lost productivity as high as $35 billion a year

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Outline the timeline of our universe

12 billion (Big Bang), 10 billion (Sun), 6 billion (Earth), 4 billion (bacteria/antibiotics), dinosaurs, humans (antibiotic use, antimicrobial resistance). Fight against bacteria (reclaim lost ground? Renegotiate boundaries?)

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Outline the drug discovery process (1)

Target selection (cellular/genetic targets, genomics, proteomics, bioinformatics). Lead discovery (synthesis/isolation, combinatorial chemistry, assay development, high throughput screening)

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Outline the drug discovery process (2)

Medicinal chemistry (library development, SAR studies, in silico screening, chemical synthesis. In vitro studies (drug affinity and selectivity, cell disease models, MOA, lead candidate refinement)

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Outline the drug discovery process (3)

In vivo studies (animal models of disease states, behavioural studies, functional imaging, ex-vivo studies). Clinical trials and therapeutics

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Outline the drug discovery process (4)

Pre-discovery (drug discovery/pre-clinical, 3-6 years). Clinical trials (6-7 years). Drug to market (0.5-2 years)

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What are the challenges of antibacterial drug discovery? (1)

If an antibacterial drug is brought to the market, the company only makes profit after 23 years of the drug being in the market. Pharmaceutical companies trying to exit antibacterial market

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What are the challenges of antibacterial drug discovery? (2)

Lack of information obtained from the Waksman protocol. More than 30 year void in discovery of new types of antibiotics. Amoxicillin can still treat 90% of infections if bacteria is not resistant against it. No diagnostic (prescribe blindly)

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What are the challenges of antibacterial drug discovery? (3)

Need to determine antibiotics to treat specific bacteria (growth culture test, 2-3 days to identify type of bacteria, drug resistant or drug sensitive bacteria)

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What are the challenges of antibacterial drug discovery? (4)

Issues with market dynamics, insurance company. Attempts to kill another organism. Bacteria will try to survive (natural selection, develop resistance). Membrane changes, additional barriers, mechanism to remove antibiotic from bacteria

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What are the challenges of antibacterial drug discovery? (5)

Despite scientific advancements - no discovery of another broad-spectrum antibiotics. Infection (caused by another organism). More successful in other disease areas (human diseases, single dose, reduced S/E)

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What is Payne's Law? (1)

Observations - target and cell based high through put screening for antibacterial agents is significantly less effective than for other targets (by a factor of five or greater)

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What is Payne's Law? (2)

This has been true for all types of targets and all types of groups doing the screening

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What is Payne's Law? (3)

Bacterial genome decoded (know all targets). Issue - application of drug discovery process to finding new antibiotic. Doesn't consider that drugs need to cross bacterial membrane, different organism/cannot make target redundant so easily

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What are the different approaches to antibiotic discovery? (1)

Phenotype based drug discovery (assay development, screening, hits/leads, target deconvolution). Target based drug discovery (target, target validation, assay development, screening, hits and leads)

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What are the different approaches to antibiotic discovery? (2)

Advantages - target linked to biological response, target is druggable, more novelty/less competition. Disadvantages - target may not be important in disease, may not be druggable, more competition/less novelty

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What are the barriers to antibiotic entry into Gram-negative bacteria?

Need to understand how bacteria works. Classification of bacteria (Gram +, Gram - through staining e.g. MRSA is Gram-positive). Gram-negative cannot be treated by current antibiotics, contains efflux pump to remove antibiotics. Bacteria mutates

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Summarise the challenges to antibacterial drug discovery (1)

Gaps in knowledge (understanding resistance, why bacteria are so tough, picking the right targets, failure to fund). Law of diminishing returns (screening the same old compounds)

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Summarise the challenges to antibacterial drug discovery (2)

Regulatory mine field (bigger yet less relevant clinical trials, labels with details but perhaps less useful information, public perception and media drivers)

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Summarise the challenges to antibacterial drug discovery (3)

Wide range of resistant bacteria, important to assess safety of drug, high dose of antibiotics needed due to efflux mechanism

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Describe features of the current antibacterial market dynamics - market saturation

Highly saturated with many similar products. Novel product success reliant on significant innovation/differentiation. Community physicians tend to stick with 2-3 products with which they are very familiar

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Describe features of the current antibacterial market dynamics - increasing generics

Increasing level of generic competition. Makes it difficult for new branded drug to compete in terms of price

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Describe features of the current antibacterial market dynamics - increasing resistance

Resistance means hospital physicians are reluctant to prescribe new drugs. Instead only use them when alternative treatments have been exhausted

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Describe features of the current antibacterial market dynamics - acute nature of disease

Infections are acute, with short treatment duration. Results in lower revenue per patient. Pharmaceuticals prefer to target chronic diseases e.g. cancer, viral infections, CNS, CV

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Describe features of the current antibacterial market dynamics

(Market saturation, increasing generics, increasing resistance and acute nature of disease lead to limited investment)

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What is a good antibacterial target? (1)

Target present in a requires spectrum of organism. Absent in humans. Essential for bacterial growth. Expressed and relevant to infection process. Function of target should be known

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What is a good antibacterial drug? (2)

When a molecule interacts with it, something bad happens to the bacterium. E.g. cell wall biosynthesis inhibition (cell lysis). Membrane integrity (cationic peptides, daptomycin). Gyrase/topoisomerase IV (double stranded DNA breaks)

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What is a good antibacterial drug? (3)

Ribosome (arrest protein synthesis e.g. tetracyclines). Essential genes (inactive) may not be good targets because small molecule inhibition is rarely total, some targets can be greater than 90% inhibition with no effect on growth

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Outline the modified phenotype based antibiotic discovery (1)

Identify new scaffold/chemical class by whole cell screen. Define spectrum of bacteria that are susceptible by screening against multi-drug resistant clinical isolates. Identify MOA in vitro

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Outline the modified phenotype based antibiotic discovery (2)

Rationalise observed biological activity using computational techniques. Assess potential for resistance to emerge. Evaluate in vivo model. Identify drug candidate for clinical evaluation

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What are the solutions for factors in the pipeline? (1)

Natural sources (unculturable organisms - culture in natural materials, inhibition quorum sensing). Optimal screening systems (little use of problem organisms - develop library of problem organisms)

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What are the solutions for factors in the pipeline? (2)

Medicinal chemistry (loss of expertise and quality - train people, enhance status/career development). Animal studies (animal activists, European legislation - change perception of politicians/public)

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What are the solutions for factors in the pipeline? (3)

Industry (reluctant/afraid of toxicity and combination - change mind set of industry). Further development (clinical trial competence - train clinicians, create clinical trial networks)

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What are the solutions for factors in the pipeline? (4)

Drug licensing (complicated/time-consuming - create special regulations for drugs active against resistant organisms). Reimbursement (unattractive for industry - implement new reimbursement systems) - doesn't suggest how to provide solutions

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Describe the proposed actions by the Pharma and Academic Community (1)

5 year plan to revive antibacterial drug discovery. Catalytic phase (years 1-2). Pilot phase (years 3-4). Implementation phase (year 5). Interaction between industry/academia, Lipinki's rule of 5

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Describe the proposed actions by the Pharma and Academic Community (2)

(option of 2 antibiotics, 1 to enter, 1 to kill, need similar PK properties). May lead to treatment similar to TB (multiple antibiotics for months - increased risk of S/E, drug interactions)

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Describe features of the catalytic phase (1)

Collect, analyse, share existing knowledge on Gram-negative drug entry and efflux. Establish a mechanism to promote exchange of antibiotic discovery knowledge, skills, expertise between sectors and across disciplines

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Describe features of the catalytic phase (2)

Carry out survey to assess feasibility and potential value of archived industry data. Establish a central repository for useful chemical matter (synthetic and natural products) for antibiotic discovery

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Describe features of the pilot phase (1)

Develop tools (quantitative assays) to quickly/accurately measure drug penetration/kinetics for Gram-negative drug entry and efflux that are independent of drug activity. Elucidate conditional guidelines for drugs targeting Gram-negative pathogens

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Describe features of the pilot phase (2)

Find alternative ways to overcome Gram-negative barriers to entry. Build prototype libraries tailored for antibacterial discovery. Determine whether single-target antibacterials can be used in combination to overcome resistance in vitro/in vivo

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Describe features of the implementation phase (1)

Scale up chemical libraries tailored for antibiotic discovery. Establish a central repository for useful chemical matter (synthetic and natural products) for antibiotic discovery

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Describe features of the implementation phase (2)

Develop proof of concept studies to accelerate the path to development for promising non-traditional therapies to treat systemic bacterial infections

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Describe the platforms for antibacterial drugs - combination therapies (1)

Resistance rapidly develops against compounds hitting a single target which automatically eliminates majority of targets. Discovery platforms increase chance of finding good lead compounds

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Describe the platforms for antibacterial drugs - combination therapies (2)

Enable development of combination therapeutics based on 2 compounds hitting 2 different targets. Makes majority of targets available to drug discovery

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Describe the platforms for antibacterial drugs - rapid dereplication with genomics and transcriptomics (1)

Natural product discovery from micro-organisms (Waksman platform - collapsed due to over-mining). Large background of known compounds makes discovery impractical

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Describe the platforms for antibacterial drugs - rapid dereplication with genomics and transcriptomics (2)

Rapid identification of targets by transcription profiling of extracts, solve problem of large background, new sources of secondary metabolites will produce discovery platforms

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Describe the platforms for antibacterial drugs - silent operons (1)

Majority of bacterial operons coding for secondary metabolites are silent/not expressed in vitro. Silent operons harbour 90% of natural product chemistry. An efficient approach for turning them on is yet to be developed

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Describe the platforms for antibacterial drugs - silent operons (2)

Combined with rapid dereplication expression from silent operons would enable a novel discovery platform

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Describe the platforms for antibacterial drugs - Waksman revival (1)

Uncultured micro-organisms make up 99% of total diversity. Methods of in situ cultivation followed by domestication will enable drug discovery from this previously inaccessible source

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Describe the platforms for antibacterial drugs - Waksman revival (2)

Combined with rapid dereplication, likely to lead to revival of Waksman platform

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Describe the platforms for antibacterial drugs - prodrugs (1)

Early screening of synthetic compounds produced mainly prodrug, suggesting high chance for their discovery. Prodrugs enter cell, activated by bacteria-specific enzyme into reactive compounds

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Describe the platforms for antibacterial drugs - prodrugs (2)

Prodrugs have increased activity against strains over-expressing activating enzymes, producing a validation test

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Describe the platforms for antibacterial drugs - species-specific compounds (1)

Early screening for anti-TB drugs produced mainly species-specific compounds. HTS of both synthetic/natural products will speed up the discovery of species-specific compounds for several pathogens

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Describe the platforms for antibacterial drugs - species-specific compounds (2)

Whole-genome sequencing of resistant mutants will identify unique targets. Rapid diagnostics with molecular methods will make treatment practical

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Describe the platforms for antibacterial drugs - rule of penetration

Envelope of Gram-negative species presents a barrier for penetration, making it difficult to discover broad-spectrum compounds. Measuring penetration of a large set of compound and ranking them will enable the deduction of rules of penetration

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Describe the platforms for antibacterial drugs - HTS and focused libraries for anti-infectives

Rules of of penetration will enable building focused libraries for discovering anti-infectives and will revive the HTS platform

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Describe the platforms for antibacterial drugs - rational design (1)

Knowing rules of penetration will revive rational design platform. Compounds will be fitted into active sites of target and rules will be taken into account when optimising a lead compound

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Describe the platforms for antibacterial drugs - rational design (2)

This will work for new projects as well as for broadening the spectrum of existing narrow-spectrum antibiotics

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Describe the re-invention of broad spectrum antibiotics (1)

Efflux is a key mediator of resistance. Traditional efflux pump inhibitor action (need high doses to inhibit efflux pump/toxic)

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Describe the re-invention of broad spectrum antibiotics (2)

Efflux pumps achieve resistance to classes of chemically related antibiotics through ensuring sub-lethal intracellular antibiotic concentrations. Traditional discrete efflux pump inhibitors compete with antibiotic compounds to bind the pump

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Describe the re-invention of broad spectrum antibiotics (3)

Allows possibility of preferential binding of antibiotic

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Describe features of ARB-antibiotic hybrids

ARB-antibiotic hybrid compounds possess EPI character in addition to antibacterial activity of parent antibiotic. Disruption of pump function allows intracellular auto-accumulation

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Antibacterial Drug Discovery

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