Antibiotic Resistance - Laura McCaughey - PDF

ANTIBIOTIC RESISTANCE LAURA MCCAUGHEY 14TH NOV 2024 LEARNING AIMS Appreciate the scale and magnitude of antibiotic resistance Understand mechanisms underlying antibiotic resistance Start to form your own opinions on the major barriers and potential solutions HISTORY & SCIENCE...

ANTIBIOTIC RESISTANCE LAURA MCCAUGHEY 14TH NOV 2024 LEARNING AIMS Appreciate the scale and magnitude of antibiotic resistance Understand mechanisms underlying antibiotic resistance Start to form your own opinions on the major barriers and potential solutions HISTORY & SCIENCE Not  Male Female TOP CAUSES OF DEATH BY AGE AND SEX IN ENGLAND & WALES, 1915 TO 2015 https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages  ANTIBIOTICS CHANGED THE WORLD Many bacterial infections could now be cured Vaccines: Poliomyelitis (polio), diptheria, tetanus, whooping cough, measles, mumps and rubella were all virtually wiped out during the second half of the 20th century, after childhood immunisation was introduced. Hygiene, sanitation and overcrowded living conditions were all improved reducing transmission rates https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages  ANTIBIOTIC DISCOVERY TIMELINE DATES INDICATED ARE THOSE OF REPORTED INITIAL DISCOVERY OR PATENT. 1943-1961 – Golden era of antibiotic discovery Screening natural products 1970’s-1980’s - target orientated screening 1990’s onwards – discovery void Silver 2011, Clinical Microbiology Reviews, 24(1),  ANTIBIOTIC DISCOVERY TIMELINE DATES INDICATED ARE THOSE OF TIME FROM REPORTED INITIAL DISCOVERY DISCOVERY TO OR PATENT. MARKET WAS MUCH SHORTER IN THE 1940’S – 1960’S DATES INDICATED ARE THOSE OF REPORTED INITIAL DISCOVERY OR PATENT. Lewis, 2017, Biochemical Pharmacology (134), 87 ANTIBIOTICS ARE THE CORNERSTONE OF MODERN MEDICINE  Antibiotics cure infections Routine surgeries rely on antibiotics to prevent/treat surgical site infections Organ transplantation relies on the use of immune system suppressing drugs, which makes patients more vulnerable to MODERN MEDICINE infection & ANTIBIOTICS Chemotherapy and other cancer treatments again affect the bodies immune system, making antibiotics essential for this patient group One of the leading causes of death in childbirth worldwide, and top 5 in the UK, is infections and sepsis*. *Sepsis is a life-threatening reaction to an infection. It happens when your immune system overreacts to an infection and starts to damage your body's own tissues and organs. – NHS: https://www.nhs.uk/conditions/sepsis/  THE PROBLEM OF ANTIBIOTIC RESISTANCE “Antibiotic resistance is happening in every region of the world and has the potential to affect anyone, of any age, in any country” – WHO report 2014 “Antibiotic resistance should be ranked along with terrorism on a list of threats to the nation” "The world is heading Sugden R (2016) Nat Microbiol;1(10):16187 - Professor Dame Sally Davies, chief towards a post- medical officer for England antibiotic era in which many common “Growing resistance among pathogens to infections will no longer antibiotics demands a coordinated global response have a cure and, once on the same scale as efforts to address climate again, kill unabated.” – Dr Margaret Chan, Director-General, change” - Dr Jeremy Farrar, Director of the Wellcome Trust WHO Quotes not THE COST OF ANTIBIOTIC RESISTANCE Antibiotic resistance was directly responsible for 1.27 million global deaths in 2019 Antibiotic resistance contributed to 4.95 million deaths in 2019 https://www.gov.uk/government/publications/health-matters-antimicrobial-resistance/health-matters-an THE COST OF ANTIBIOTIC RESISTANCE Antibiotic resistance was directly responsible for 1.27 million global deaths in 2019 Antibiotic resistance contributed to 4.95 million deaths in 2019 Antibiotic resistance affects countries in all regions and at all income levels, but poverty & inequality exacerbates the drivers and consequences https://www.gov.uk/government/publications/health-matters-antimicrobial-resistance/health-matters-an THE CAUSES OF ANTIBIOTIC RESISTANCE OVER-PRESCRIBING OF ANTIBIOTICS The more antibiotic there is in the environment the more likely bacteria are to encounter the antibiotic and then develop resistance In the UK, at least 20% of antibiotic prescriptions in primary care are estimated to be unnecessary To bring down prescription rates in the UK and globally we need to: educate the public on the uses of antibiotics Invest in rapid diagnostic tests to help identify quickly if antibiotics are actually needed Have more regulated use of antibiotics globally PATIENTS NOT FINISHING THEIR ANTIBIOTIC TREATMENT Bacteria take advantage of any opportunity to multiply As they multiply, they can mutate Low level of antibiotic not enough to kill the bateria or stop it growing can still promote the evelopment of resistance Completing the full course helps ensure that as many bacteria as possible are eradicated, reducing the chance that any resistant bacteria survive to develop and spread Slide not examinable – for information only OVER-USE AND MIS-USE OF ANTIBIOTICS IN LIVESTOCK AND FISH FARMING Slide not examinable – for information only LACK OF HYGIENE AND POOR SANITATION Poor hygiene and sanitation: makes more people sick and increases the need for antibiotics provides more opportunity for resistant bacteria to develop and spread Slide not examinable – for information only POOR INFECTION CONTROL IN HOSPITALS AND CLINICS Hand hygiene is the most important way of preventing the spread of infections including antibiotic resistant infections Slide not examinable – for information only LACK OF NEW ANTIBIOTICS BEING DEVELOPED Pharma companies are profit making organisations Antibiotics have always been very cheap, effective (single course) and therefore not good at generating revenues Contrast to chronic conditions: arthritis, blood pressure or long terms conditions like HIV HOW DO ANTIBIOTICS WORK  HOW DO ANTIBIOTICS WORK Nucleic acid synthesis: target the machinery that makes DNA and RNA Ribosomal function: target the machinery that produces proteins, such as the ribosome and associated proteins Cell wall: target the synthesis of the cell wall Cell membrane: target the plasma membrane integrity of the bacterial cell Inhibition of cell metabolism and growth: inhibit folic acid biosynthesis and oxidative phosphorylation of ATP synthase Antibiotic names in each target not EXAMPLE: B-LACTAM ANTIBIOTICS Beta-lactam antibiotics work by binding to penicillin-binding proteins (PBPs) in bacteria, which prevents the cross-linking of the peptidoglycan layer of the bacterial cell wall https://en.wikipedia.org/wiki/Penicillin-binding_proteins#/media/  EXAMPLE: B-LACTAM ANTIBIOTICS v v v Lipopolysaccharide Outer membrane Peptidoglycan layer Inner membrane v The bacteria swells, ruptures, and dies due to an osmotic gradient. Yao (2012) Molecular Cell, Volume 48, Issue 5, 705 – 712 / Wong (2021) Front. Microbiol., Vol 12n  Homer. 2024, Nat Rev Bioeng doi.org/10.1038/s44222-0 HOW DOES ANTIBIOTIC RESISTANCE WORK Types of resistance: Intrinsic Acquired Mechanisms of resistance: Reduced drug uptake Enzymatic degradation Target modification Increased drug efflux Antibiotic names in each mechanism not EXAMPLE: B-LACTAM ANTIBIOTICS Zhang (2024 Antibiotics 2024, 13(3), 260; HOW QUICKLY DOES RESISTANCE DEVELOP SPEED OF ANTIBIOTIC RESISTANCE Alvarez-Martinex (2021) Sci Rep 11, 588 (2021). https://doi.org/10.1038/s415  RESISTANCE: HOW DOES IT HAPPEN? The video shows bacteria spreading across a 2 ft by 4 ft agar plate with nine bands of increasing antibiotic concentrations (0, 1, 10, 100, 1000, 100, 10, 1, 0 x MIC). The bacteria spread until they reached a concentration where they could no longer grow. At each concentration, a small group of bacteria adapted and survived, and eventually the bacteria spread to the highest concentration of antibiotic (1000 x MIC) after 11 days. MIC: Minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent that https://www.youtube.com/watch? prevents the visible growth of a microorganism after an  WHAT IS BEING DONE TO TACKLE THE PROBLEM? Dr Colin Miles, Head of Strategy, Advanced Manufacturing and Clean Growth at UKRI, said: “Tackling the creeping pandemic of anti-microbial resistance – increasing resistance to antibiotics – is a large, complex problem. Ten million people each year are expected to lose their lives to it by 2050. Rather than taking single-discipline approaches, we need researchers from across disciplines to come together and look at all aspects of the problem – from human behaviour and how we grow crops and rear animals for consumption to how we manage the environment or use technology, clinical management strategies and challenging established Quote not cultural norms.” examinable https://www.ukri.org/news/new-research-networks-will-tackle-antimicrobial-resistance/ https://amr-review.org/ LECTURE SUMMARY/TAKE HOME MESSAGES – CREATED BY CHATGPT FROM SLIDE TRANSCRIPT 1.Discovery of Penicillin: Alexander Fleming discovered penicillin in 1928, observing its ability to kill bacteria. However, it was Florey, Chain, and Heatley who developed it further, leading to the first successful treatments in animals and humans by 1940-41. Unfortunately, penicillin was initially in short supply, limiting its use. 2.Impact of Antibiotics: The introduction of antibiotics revolutionised healthcare, drastically reducing deaths from infections. They are essential for treating bacterial infections, preventing infections in surgeries, supporting organ transplants, and treating cancer patients with weakened immune systems. 3.Decline of Infections as Leading Death Cause: Improved hygiene, sanitation, vaccines, and antibiotics greatly reduced infection-related deaths by the 1960s. These advances, alongside antibiotics, transformed public health. 4.Golden Era and Decline in Discovery: The “golden era” of antibiotic discovery (1943-1961) yielded many effective antibiotics, but innovation slowed after the 1970s, creating a void in new antibiotic development. 5.Antibiotic Resistance: Overuse and misuse of antibiotics have led to antibiotic resistance, posing a major global threat. Resistance is fueled by factors like incomplete courses of antibiotics, overuse in farming, poor infection control, and lack of new antibiotic development. 6.Mechanics of Antibiotic Function and Resistance Development: Antibiotics target various bacterial functions, such as cell wall synthesis and protein production. Bacteria’s ability to develop resistance is a natural process, but its acceleration due to human activity threatens modern medicine. 7.Mechanisms of Resistance: Bacteria can resist antibiotics through several mechanisms: reducing drug uptake, enzymatic degradation of antibiotics, modifying targets, and using efflux pumps to expel antibiotics. 8.Urgency of the Resistance Crisis: Antibiotic resistance is projected to cause 10 million deaths annually by 2050 if not addressed, with severe economic impacts. It’s a global issue, especially affecting low- and middle-income countries. In essence, antibiotics are essential for modern healthcare, but their effectiveness is under threat due to rising resistance. Preventing misuse and encouraging new antibiotic development are critical for preserving their life-saving potential.  B-lactam antibiotics target DNA replication. True TEST YOUR KNOWLEDGE or false? - False Antibiotic resistance is inevitable. True or What is antibiotic resistance? false? When bacteria are naturally resistant to antibiotic(s) - True (intrinsic resistance) or when bacteria develop resistance mechanisms, through mutation or gene Antibiotic use leads to antibiotic resistance. transfer, to one or more antibiotics (acquired True or false? resistance) - True Name the four main resistance mechanisms used The golden era of antibiotic discovery was by bacteria: when? Reduced drug uptake a) 1920’-1930’s Enzymatic degradation b) 1990’s onwards Target modification c) 1940’-1960’s Increased drug efflux d) 1930’s-1940’s What is the difference between intrinsic and Which TWO of these is not a cause of ABR? acquired resistance? e) over-prescribing of antibiotics - Intrinsic resistance is when a microorganism is f) patients finishing their antibiotic treatment naturally resistant to a substance, for example some g) lack of hygiene and poor sanitation bacteria don't have cell walls, like mycoplasma so h) Development of vaccines antibiotics that prevent cell-wall building like beta   https://theconversation.com/we-know-why-bacteria-become -resistant-to-antibiotics-but-how-does-this-actually-happen-5 WANT TO READ 9891 MORE & GET INVOLVED?  https://theconversation.com/five-of-the-scariest-antibiotic-re sistant-bacteria-in-the-past-five-years-100654  https://www.youtube.com/watch?v=Lg7nH7bzzF8  3 min video of me in the FameLab Australia National semi-finals talking about antibiotic resistance and my research on protein antibiotics  https://www.ukri.org/news/new-research-networks-will-tackl e-antimicrobial-resistance/  Eight new networks, combining different research specialisms, will work together to tackle one of humanity’s biggest threats, antimicrobial resistance (AMR)  https://wellcome.org/news/explained-history-progress-tackli Not ONLY MOVE ONTO THE NEXT SLIDE IF YOU WANT THE ANSWERS TO THE ‘TEST YOUR KNOWLEDGE’ QUESTIONS  B-lactam antibiotics target DNA replication. True TEST YOUR KNOWLEDGE or false? - False Antibiotic resistance is inevitable. True or What is antibiotic resistance? false? When bacteria are naturally resistant to antibiotic(s) - True (intrinsic resistance) or when bacteria develop resistance mechanisms, through mutation or gene Antibiotic use leads to antibiotic resistance. transfer, to one or more antibiotics (acquired True or false? resistance) - True Name the four main resistance mechanisms used The golden era of antibiotic discovery was by bacteria: when? Reduced drug uptake a) 1920’-1930’s Enzymatic degradation b) 1990’s onwards Target modification c) 1940’-1960’s Increased drug efflux d) 1930’s-1940’s What is the difference between intrinsic and Which TWO of these is not a cause of ABR? acquired resistance? e) over-prescribing of antibiotics - Intrinsic resistance is when a microorganism is f) patients finishing their antibiotic treatment naturally resistant to a substance, for example some g) lack of hygiene and poor sanitation bacteria don't have cell walls, like mycoplasma so h) Development of vaccines antibiotics that prevent cell-wall building like beta