English subtitles for clip: File:Why won’t antibiotics cure us anymore.webm

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it's estimated that antibiotics have

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saved about 200 million lives since

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their introduction

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but the future of antibiotics doesn't

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look good if we don't act now

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why won't antibiotics cure us anymore

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this is the university of the

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netherlands

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i would like to start by asking a

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question what

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is the most valuable naturally occurring

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material

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you're probably thinking about gold or

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diamonds right now and if you think

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about the word valuable in terms of

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monetary worth

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you're probably right but how many lives

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has gold ever saved

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gold or diamonds are not capable of

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preventing or curing diseases

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in that sense monetary worth is a rather

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poor gauge of real value

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so to focus the question i would ask

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what naturally occurring substance has

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delivered the greatest benefit to human

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health

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well as the topic of this talk might

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suggest it's antibiotics

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at least in my eyes let's go back to the

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year 1900

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for people born in europe in 1900 the

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average life expectancy was 42.7 years

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while today heart disease and cancer

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present the leading causes of death

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100 years ago infectious disease was the

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biggest killer

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at that time bacterial diseases like

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cholera diphtheria pneumonia

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tuberculosis and typhus were rampant

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claiming the lives of young and old

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alike

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this dramatically changed with the

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widespread introduction of antibiotics

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in the mid-1940s

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as you might know antibiotics

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specifically kill bacteria

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including those responsible for causing

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infectious diseases

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with the availability of antibiotics

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average life expectancy rose

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sharply in the 20th century it is

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estimated that since their introduction

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more than 200 million lives have been

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saved thanks to antibiotics

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but how were antibiotics discovered and

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what exactly are antibiotics

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well as the story goes the scottish

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biologist

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alexander fleming discovered the first

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major class of antibiotics called the

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penicillins

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in 1928 the best part of the story he

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discovered penicillin by accident

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fleming was doing research on bacteria

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in his lab

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before he left to go on holiday that

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summer he placed a bacterium called

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staphylococci

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on some petri dishes so the bacteria

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could grow in the weeks that he was away

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from the lab

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this is a petri dish filled with agar

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agar is a gel-like substance that

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bacteria can eat and grow on

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fleming worked with petri dishes just

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like this after adding bacteria to the

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agar and waiting some days

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the results would generally look like

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this here you can clearly see

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that the bacteria have grown where

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they've been streaked out on this agar

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however when he returned from his

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holiday fleming noticed that one petri

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dish had become contaminated with the

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fungus

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and that in the area immediately

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surrounding the fungus the bacteria had

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been killed

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at that huge historic extraordinary

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moment fleming spoke those famous words

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that's funny in fact the story of

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fleming's chance discovery

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inspired popular science writer isaac

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asimov to pen his famous quote

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the most exciting phrase to hear in

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science the one that herald's new

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discoveries is not

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eureka but that's funny

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fleming went on to make the

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all-important connection he hypothesized

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that the fungus that had contaminated

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his experiment

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was producing and excreting a substance

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that killed bacteria

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that substance penicillin

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as you can see in this petri dish from

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my lab when a tiny drop

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of pure penicillin is added to the agar

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it very clearly prevents

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bacterial growth a very nice

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reproduction of fleming's experiment

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now just as any good scientist does back

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in 1928 fleming described his new

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scientific discovery in a paper that he

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submitted for publication

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however the impact of his discovery was

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not immediately clear to the scientific

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community

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in fact fleming's discovery floundered

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in obscurity for more than a decade

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in fact it was the second world war that

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led penicillin to be transformed

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from an academic curiosity into a

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life-saving medicine

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with financial backing from major drug

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companies and the governments of the

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united states and great britain

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the large-scale production of penicillin

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was realized within four years

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when the allies landed on the beaches at

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normandy in 1944

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they carried with them one million doses

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of penicillin this gave them a

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significant advantage in the treatment

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of battlefield infections against the

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germans

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who had not been successful in

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developing effective antibiotics

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the success of penicillin ignited the

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hunt for other naturally occurring

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antibiotics

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as i told you penicillin was discovered

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as the product of a fungus

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people then began to hunt for other

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microorganisms that might also produce

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antibiotics

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what followed was the golden age of

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antibiotic discovery

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a 20-year period spanning the mid-1940s

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to the mid-1960s

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where the majority of the antibiotics we

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still use today were brought to the

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clinic

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i would like to emphasize that it really

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is astonishing that so many naturally

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occurring antibiotics can be used

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directly as medicines

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as is it's quite remarkable that a

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compound made by a soil dwelling fungus

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or bacteria for its own purposes can

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also work as a medicine in the human

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body

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it's actually very difficult for

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medicines to do what they're meant to do

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in our bodies

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and it is for this reason that most

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other medicines take years to be

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perfected

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in contrast many of the antibiotics

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discovered in the golden age work

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extremely well in humans very much a

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case of nature delivering us a gift on a

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silver platter

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by the 1970s the readily abundant safe

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and effective naturally occurring

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antibiotics had been found

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the so-called low-hanging fruit had been

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plucked

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thanks to a broad arsenal of new

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antibiotics bacterial infections were

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then largely deemed to be under control

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as a result the focus of drug developers

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began to shift to other disease areas

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that had comparatively fewer therapeutic

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options

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areas like cancer heart disease and

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neurodegenerative disease

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this in turn led to a marked decrease in

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the discovery of new antibiotics

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in fact over the last 50 years only two

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new classes of antibiotics have been

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brought to the clinic

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it boggles my mind to think that the

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vast majority of the antibiotics that we

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still use today

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were discovered before i was even born

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you might think

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so what it's great that we've been using

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all these naturally occurring

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antibiotics for so long we don't need

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any new ones because they're working

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just fine

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well you would be wrong the so-called

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discovery void in antibiotic

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discovery is actually quite worrisome

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particularly in light of an issue you

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might be familiar with

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the emerging threat of antibiotic

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resistance

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today life-threatening infections are on

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the rise as many bacteria have developed

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the ability

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to resist the action of antibiotics this

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means the antibiotics we have

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don't kill bacteria they are supposed to

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anymore

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globally each year seven hundred

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thousand deaths are now attributed to

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infections caused by drug resistant

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bacteria

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notably many of these infections might

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have been treatable in the 1960s and

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1970s

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before the bacteria causing the

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infections developed resistance

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to be clear this means that there are

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some infections caused by bacteria that

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were treatable with antibiotics 20 or 30

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years ago

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but today are very difficult or even

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impossible to treat

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if this carries on we will have a

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serious problem people can die

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healthcare is at risk of moving

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backwards instead of forwards

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consider also the critically important

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role that antibiotics play in many

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routine medical procedures

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thanks to antibiotics surgeries can be

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performed without threat of infection

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also antibiotics provide a protective

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shield for immune compromised patients

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receiving chemotherapy

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without effective antibiotics such

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procedures become much more risky

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and potentially life-threatening in fact

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recent projections suggest that without

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serious investment and innovation in the

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field

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by the year 2050 antibiotic resistance

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may claim as many as 10 million lives

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per year

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more deaths than caused by all cancers

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combined

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where does antibiotic resistance come

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from well one of the main causes of

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antibiotic resistance

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is the process of genetic mutation

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mutations in the genes of bacteria occur

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spontaneously

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at a rate of about 1 in 10 million a

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bacterial infection represents a

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population of billions and billions of

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single-celled bacteria

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due to spontaneous mutation there will

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always be a few cells that differ

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slightly from the others

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and in some cases a mutation can allow a

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bacterium to resist the effect of an

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antibiotic

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for example a mutation that changes the

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structure of a bacterial protein that is

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the target of an antibiotic

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can significantly reduce the effect of

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that antibiotic

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here you see two bacterial cells on the

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left is a cell with a normal bacterial

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protein in it

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and on the right you see a mutated cell

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where the target protein has now been

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changed and has a different shape

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the antibiotic here is the yellow

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triangle and as you can see the

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antibiotic will work

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on the normal cells it fits or binds to

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the normal bacterial protein

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allowing the antibiotic to do its job

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and kill the bacteria

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but in the mutated cell the antibiotic

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cannot bind its target

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and therefore doesn't work this cell is

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resistant

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such a mutation will initially only

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impart a small number of bacteria with

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disadvantage

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while the vast majority of the other

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cells remain sensitive to the antibiotic

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bacteria however reproduce at an amazing

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rate in some cases doubling their

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population within 20 minutes

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this means that initially small

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subpopulation of resistant mutated

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bacteria

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can over a period of hours become the

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dominant player in an antibiotic

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resistant infection

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in this animation you will see that the

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cells with the blue bacterial protein

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are disappearing because the antibiotic

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is killing them but the cell with the

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red bacterial protein will not be killed

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and is therefore able to reproduce this

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process

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of acquired antibiotic resistance and

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the threat it poses

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was in fact predicted by fleming himself

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in 1945.

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fleming then stated it is not difficult

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to make microbes resistant to penicillin

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by exposing them to concentrations

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not sufficient to kill them there is the

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danger that a man may underdose himself

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and by exposing his microbes to

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non-lethal quantities of the drug

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make them resistant the impact of our

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enormous use of antibiotics has created

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precisely the scenario fleming warned

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against

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since the mid 20th century we have

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injected huge quantities of antibiotics

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into our environment

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around the world antibiotics are used

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not only to treat serious infections in

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humans

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but also on a much larger scale in the

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agricultural industry

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where antibiotics are added to animal

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feed interestingly

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antibiotics do not only protect animals

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from infection

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antibiotics also cause animals to grow

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larger faster

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regular exposure to antibiotics both

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inside and outside of hospital settings

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provide bacteria with precisely the

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conditions required for resistance

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development

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if they are exposed to antibiotics

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frequently bacteria have more

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opportunity to get used to them

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leading to more resistant cells and

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antibiotic resistance

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so while our use of antibiotics is vital

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to maintaining effective health care it

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has also led us into uncharted territory

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as a species

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we are currently in the midst of a

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massive real-time biological experiment

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how resistance rates will increase in

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the coming decades is difficult to

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predict

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but the need for action is clear

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okay so what can we do about this one

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approach

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is to reduce our use of antibiotics this

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approach can indeed slow the rate at

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which resistance appears

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it is clear however that we cannot

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completely eliminate our use of

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antibiotics

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effective antibacterial therapies will

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continue to be a cornerstone of our

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medical system

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so we have to look for other solutions i

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will discuss three such solutions being

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pursued by my research group

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the first solution is enhancing

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antibiotic molecules

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let me explain what that means in our

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research my team uses organic chemistry

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to structurally modify naturally

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occurring antibiotics

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this means that we can change or adjust

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the molecular structure of an antibiotic

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so that we can enhance its antibacterial

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properties let me give you an example

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in the lab we have found a way to

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enhance the naturally occurring

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antibiotic vancomycin

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so it can overcome resistance on the

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left you see the normal molecule of

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vancomycin and on the right

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you can see that something has been

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added these circles represent new

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structural features that can chemically

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that we can chemically attach

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to the vancomycin molecule in doing so

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we have discovered new variants of

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vancomycin that are supercharged

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with activities thousands of times

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higher than normal vancomycin

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these new supervancomycins work against

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vancomycin-resistant bacteria

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00:12:37,279 --> 00:12:41,920
let's move on to a second solution we

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can also build antibiotics from scratch

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in fact in some cases this can be easier

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than trying to isolate an antibiotic

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from natural sources

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for example some naturally occurring

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00:12:49,680 --> 00:12:53,120
antibiotics are only produced in very

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low quantities

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in other cases a promising naturally

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00:12:55,040 --> 00:12:58,719
occurring antibiotic

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00:12:56,240 --> 00:12:59,440
might also be toxic to humans as a

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00:12:58,720 --> 00:13:01,040
solution

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00:12:59,440 --> 00:13:02,480
we can in some cases build these

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00:13:01,040 --> 00:13:05,439
molecules from scratch

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in the lab as illustrated here if an

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antibiotic

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00:13:06,000 --> 00:13:09,200
is difficult to obtain from nature

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00:13:07,600 --> 00:13:10,880
chemical synthesis can provide much

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greater amounts of material

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also with this approach we can make new

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variants with improved properties

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00:13:14,880 --> 00:13:18,880
as you can see in the image we can

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change certain parts of the antibiotic

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00:13:18,880 --> 00:13:22,720
by doing so it may be possible to

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00:13:20,800 --> 00:13:25,839
improve antibacterial activity

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00:13:22,720 --> 00:13:26,240
or reduce toxicity and last but not

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00:13:25,839 --> 00:13:28,320
least

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we are working on resistance breakers

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00:13:28,320 --> 00:13:32,000
this means we are disabling or blocking

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antibiotic resistance mechanisms

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themselves

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again let me give you an example some

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00:13:35,519 --> 00:13:39,040
bacteria called gram negatives

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have an extra outer membrane that can

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prevent antibiotics from entering the

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00:13:40,880 --> 00:13:44,000
cell

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00:13:41,839 --> 00:13:46,800
in this way gram-negative bacteria are

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00:13:44,000 --> 00:13:48,399
inherently resistant to many antibiotics

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00:13:46,800 --> 00:13:50,479
we are working on taking that outer

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membrane down as a means of sensitizing

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00:13:50,480 --> 00:13:54,800
them to antibiotics

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00:13:52,560 --> 00:13:56,399
if we focus on solutions like these i am

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optimistic that we can stay ahead of

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00:13:56,399 --> 00:14:00,880
antibiotic resistance

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00:13:58,800 --> 00:14:02,880
so as i hope i've made clear in this

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00:14:00,880 --> 00:14:04,639
talk antibiotics are one of the most

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00:14:02,880 --> 00:14:06,399
valuable natural resources we have ever

451
00:14:04,639 --> 00:14:09,360
discovered as a human species

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00:14:06,399 --> 00:14:11,279
they truly are lifesavers however

453
00:14:09,360 --> 00:14:12,320
antibiotic resistance is a serious

454
00:14:11,279 --> 00:14:14,160
problem

455
00:14:12,320 --> 00:14:16,079
and we are in great danger if we don't

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00:14:14,160 --> 00:14:17,839
act to address it now

457
00:14:16,079 --> 00:14:19,359
the low-hanging fruit in antibiotics was

458
00:14:17,839 --> 00:14:21,360
plucked long ago

459
00:14:19,360 --> 00:14:24,079
thankfully today we have new insights

460
00:14:21,360 --> 00:14:25,839
and technologies to find new antibiotics

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00:14:24,079 --> 00:14:27,680
in leiden i guide a team of talented

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00:14:25,839 --> 00:14:28,880
researchers who are dedicated to finding

463
00:14:27,680 --> 00:14:30,638
new solutions to the problem of

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00:14:28,880 --> 00:14:32,639
antibiotic resistance

465
00:14:30,639 --> 00:14:34,480
every day in the lab i keep my ears open

466
00:14:32,639 --> 00:14:35,600
in case i hear someone say those famous

467
00:14:34,480 --> 00:14:45,290
words

468
00:14:35,600 --> 00:14:48,919
that's funny thank you

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00:14:45,290 --> 00:14:48,919
[Music]

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00:14:50,880 --> 00:14:52,959
you