Antibiotic Resistance

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Domenic Warner
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1 Preparing for the Battle Antibiotic Resistance Joy Jiao Systems Biology, Harvard University

2 World Health Organization Global Report on Antibiotic Resistance, 01: resistance to common bacteria has reached alarming levels few, if any, of the available treatments options remain effective for common infections

3 Battle Plan 1 Understand the enemy Attack and counterattack Intelligence from the frontlines Join the fight

4 Battle Plan Understand the enemy Meet your microbes Attack and counterattack Intelligence from the frontlines Join the fight

5 Bacteria are very small

6 They outnumber us 1 >10:1 on our bodies 1. Berg, R. Trends in Microbiology, 1996

7 1 They can be helpful S. epidermidis inhibits S. aureus 1 colonization Skin Cells Iwase et al, Nature 010

8 1 They can be helpful Bacteria in the large intestine help us digest food, and produce useful compounds such as vitamins Intestinal Cell

9 1 They can be helpful Bacteria in the gut are important for training the immune system Immune Cell

10 1 1 Not all bacteria are good CLOSTRIDIUM DIFFICILE 50,000 Infections/ year ENTEROBACTERIACEAE 9,000 Infections/year Graphics and data adapted from CDC Report on Antibiotic Resistance, 01 NEISSERIA GONORRHOEAE 6,000 Infections/year

11 Not all bacteria are good 1 Each year, antibiotic resistant microbes cause at least,09, illnesses,000 deaths Graphics and data adapted from CDC Report on Antibiotic Resistance, 01

12 Battle Plan 1 Understanding the enemy Attack and counterattack History of antibiotics How antibiotics work What causes antibiotic resistance? Intelligence from the frontlines Join the fight

org/wiki/penicillin Plate image adapted from:

13 1 Antibiotics revolutionized medicine Photo: Plate image adapted from: Alexander Flemming discovered Penicillin in 198

14 Antibiotics target critical processes in the cell

15 Antibiotics target critical processes in the cell DNA Replication Fluoroquinolones Adapted from

16 Antibiotics target critical processes in the cell Rifamycin RNA Transcription Adapted from

17 Antibiotics target critical processes in the cell Tetracycline Protein Synthesis Adapted from

18 Antibiotics target critical processes in the cell Penicillin Cell Wall Synthesis Adapted from

20 Our antibiotics are losing effectiveness against Neisseria Gonorrhoeae CDC Report on antibiotic resistance, 01

21 How did this happen? Adapted from Clatworthy et al, Nature ChemBio, 007

22 How did this happen? EVOLUTION Adapted from Clatworthy et al, Nature ChemBio, 007

23 Replication errors create diversity within a population

24 Replication errors create diversity within a population Resistant mutant

25 1 Bacteria share genes via horizontal gene transfer Many important genes for antibiotic resistance can be found on PLASMIDS mobile DNA elements that can easily jump between species

26 Antibiotics kill off the sensitive cells, allowing resistant cells to take over Initial sensitive population with rare resistant cell

27 Antibiotics kill off the sensitive cells, allowing resistant cells to take over Initial sensitive population with rare resistant cell Antibiotics kill sensitive cells, but not resistant cells

28 Antibiotics kill off the sensitive cells, allowing resistant cells to take over Initial sensitive population with rare resistant cell Antibiotics kill sensitive cells, but not resistant cells Resistant cells take over the population

29 Questions? CDC Report on antibiotic resistance, 01

30 Battle Plan 1 Understanding the enemy Attack and counterattack Intelligence from the frontlines Better Stewardship New antibiotics Diagnostics Join the fight

31 Conserve what we have left: better Stewardship ~90% of antibiotics used in the US are for agricultural production 1 Antibiotics used as growth promoters in livestock production: Bambermycin Lasalocid Monensin Salinomycin Virginiamycin Bacitracin 1. Union of Concerned Scientists Reinhardt, Merck Veterinary Manual, 01

32 Conserve what we have left: better Stewardship Antibiotic use in agriculture has been shown to generate resistant bacteria which can then spread to humans In 01, the FDA imposed voluntary guidelines for phasing out certain antibiotics in livestock feed Wegener, Curr Opinion in Microbiol. 00 Knox, npr.org, 01 Carlet, Antimicrobial Resistance and Infectino Control, 01

33 Conserve what we have left: better Stewardship As much as 50% of antibiotics prescriptions are unnecessary or misused Hospitals are working to: Make sure to culture bacteria for identification before starting antibiotic treatment Give clear dosage and duration instructions Reassess effectiveness in - days CDC Report on antibiotic resistance, 01

34 Battle Plan 1 Understanding the enemy Attack and counterattack Intelligence from the frontlines Better Stewardship New antibiotics Diagnostics Join the fight

35 We are discovering fewer and fewer antibiotics Graphics and data adapted from CDC Report on Antibiotic Resistance, 01

to grow and are difficult to grow in the laboratory The ichip, introduced in 010, can grow

36 Sorting through dirt for new antibiotics Through millenia of microbial warfare, soil bacteria have developed the majority of antibiotics Many microbes need support from the soil community to grow and are difficult to grow in the laboratory The ichip, introduced in 010, can grow previously uncultured bacteria Teixobactin, 015 Nichols et al, ACM, 010 Ling et al, Nature, 015

37 1 New diagnostics for fast detection Many pathogens grow very slowly in the lab Knowing what antibiotics they are resistant to is time-sensitive Don t waste time using the wrong antibiotics Don t allow further resistance to develop New methods for fast diagnosis based on detection of microbial DNA can significantly speed up this process

38 Battle Plan 1 Understanding the enemy Attack and counterattack Intelligence from the frontlines Join the fight

39 The CDC recommends: Tactic #1 Prevent infections by practicing good hand hygiene

40 The CDC recommends: Tactic # DO NOT ask for antibiotics when your doctor thinks you do not need them (ex. viral infections)

41 Antibiotics cannot kill viruses Bacteria: complex cell with DNA replication, transcription, translation Virus: a packet of DNA

42 The CDC recommends: Tactic # Always use antibiotics for full duration prescribed

43 What doesn t kill you makes you more resistant Initial sensitive population with rare resistant cell

44 What doesn t kill you makes you more resistant Initial sensitive population with rare resistant cell Antibiotics kill sensitive cells quickly, and slightly resistant cells slowly. Therapy eventually eradicates all cells.

45 What doesn t kill you makes you more resistant Premature end of antibiotics therapy allow slightly resistant cells to take over, and possibly gain increased resistance Initial sensitive population with rare resistant cell

46 Battle Plan 1 Understand the enemy Attack and counterattack Intelligence from the frontlines Join the fight 90% 50% Livestock Incorrect 1. DO Wash your hands. DON T take antibiotics for viral infections. DON T skip prescribed antibiotics

47 Thank you! SITN would like to acknowledge the following organizations for their generous support of this event.

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Lecture 6: Fungi, antibiotics and bacterial infections Outline Eukaryotes and Prokaryotes Viruses Bacteria Antibiotics Antibiotic resistance Lecture 1 2 3 Lecture Outline Section 4 Willow and aspirin Opium