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Thursday, May 10, 2018

The Opioid Crisis and Quest for Superior Analgesics without AddictionCo-produced with the ACS Division of Medicinal Chemistry


Writing Competitive Research Proposals that Win FundingCo-produced with the ACS Graduate & Postdoctoral Scholars Office and the ACS Office of Research Grants

Chemical Entity and Biomolecule Scientific Program Tracks:

• Preclinical (including Discovery)• Bioanalytical• Clinical Pharmacology• Manufacturing & Bioprocessing• Formulation & Quality

YouTube video: https://www.youtube.com/watch?v=1DOxLBg0Ouw

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11Find out more about the ACS MEDI Division! www.acsmedchem.org

Join the Division Today!

For $25 ($10 for students), You Will Receive:

• A free digital copy of our annual medicinal chemistry review volume (over 600 pages, $160 retail price)

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12https://pubs.acs.org/journal/bcches

Journal Scope

Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecularconjugates.

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Co-produced with the ACS Division of Medicinal Chemistry and the American Association of Pharmaceutical Scientists13

www.acs.org/acswebinarsSlides available now and an invitation to view the recording will be sent when available.

Nanomaterials for Fighting Antibiotic-Resistant BacteriaSession 4 of the 2018 Drug Design and Delivery Symposium

Christopher EnglandManaging Editor, ACS Combinatorial Science,

ACS Synthetic Biology, Bioconjugate Chemistry, and Molecular Pharmaceutics

Vincent RotelloProfessor of Chemistry and a University Distinguished Professor, University of

Massachusetts at Amherst,Editor-in-Chief, Bioconjugate Chemistry

Nanomaterials for Fighting Antibiotic-Resistant Bacteria

I) Antibiotic-resistant bacteria

a) Planktonic (what’s that?)

b) Biofilms

II) Antimicrobial nanomaterials

a) Carriers for antibiotics

b) Antimicrobial nanoparticles

c) Combination therapies

14

Vincent RotelloUniversity of Massachusetts

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EXACTLY HOW BAD IS ANTIBIOTIC

RESISTANCE RIGHT NOW?A WOMAN IN THE US RECENTLY DIED FROM A SUPERBUG THAT NO

ANTIBIOTICS COULD TREAT

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• 100,000

• 275,000

• 400,000

• 700,000

• 1,000,000

How many people die each year world-wide from antibiotic-resistant bacterial infections?

Audience Challenge QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

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What is bacterial resistance?

Survival of the fittest!

https://www.cdc.gov/drugresistance/about.html

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What are MDR bacteria?

• MDR=Multi-Drug Resistant

• Bacteria rapidly gain

resistance to antibiotics

• How rapidly?

18

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How do bacteria become resistant so rapidly?

• Let’s think about where antibiotics come from

• Antibiotics are weapons in a billions-year war…

• …between bacteria, fungi, and other organisms

• Step 1: Pump drugs out

• Step 2: Plasmids—DNA blueprints for different defenses

developed through the ages

• That can be shuffled to counter shuffled attacks

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Planktonic bacteria infections

• Planktonic = dispersed

• Blood infections (e.g. bacterial sepsis)

• Intestinal distress…

• Essentially all infections at the start

20

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How do we treat planktonic infections?

• Our immune system

• Topical antimicrobials (surfactants, alcohol, peroxide)

Toxic to us, so external use only

• Antibiotics

Work really well, until resistance is encountered!

21

Nanomaterials for fighting planktonic bacteria

• New properties = new strategies

• Basic nano—NPs have high surface to volume ratio

• The key to activity of silver nanoparticle antimicrobials

• Silver ions inhibit multiple cell wall enzymes

• AgNPs are widely used (medical, textile…)

• And bacteria are starting to show tolerance/resistance

22

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AgNPs + light = synergistic photodynamic therapy

• Graphene used as platform

• AgNPs generate reactive oxygen species (ROS) on irradiation

• Particle + hn = quick killing

• Particle +dark = slow killing

Xie, X.; Mao, C.; Liu, X.; Zhang, Y.; Cui, Z.; Yang, X.;

Yeung, K. W. K.; Pan, H.; Chu, P. K.; Wu, S.

ACS Appl. Mater. Interfaces 2017, 9, 26417-26428.

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Nanomaterials as antimicrobial platforms

• Let’s start with NPs as carriers

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• Engineered NP surfaces provide multiple features

• NPs can be carriers and therapeutics

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Nanomaterials as antibiotic carriers

• High surface to volume ratio (again)

• with multivalent presentation of vancomycin

• 60-fold lower minimum inhibitory (MIC) concentration than free drug

25

Lysing bacteria using multivalent cationic NPs

• Cationic lipids lyse/kill bacteria (e.g. Lysol)

• What happens if there are a lot of ’em?Strain Species MIC (nM)

# of resistant

drugsMDR

CD-2 E. coli 16 1 No

CD-496 E. coli 16 2 Yes




CD-866E. cloacae

complex16 2 Yes

CD-1412E. cloacae

complex8 4 Yes

CD-1545E. cloacae

complex16 7 Yes

CD-1006 P. aeruginosa 16 1 No

CD-23 P. aeruginosa 32 13 Yes

CD-1578 S. aureus 64 4 Yes

CD-489S. aureus -

MRSA32 10 Yes

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• 60-fold lower minimum inhibitory concentration (MIC) with hydrophobic headgroups

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How do cationic NPs work, and what about specificity?

• Membrane damage demonstrated by dye penetration

• ~50-fold less toxic to mammalian cells and RBCs

• Interesting, but not amazing therapeutic index...

Li, X. N.; Robinson, S. M.; Gupta, A.; Saha, K.;

Jiang, Z. W.; Moyano, D. F.; Sahar, A.; Riley, M. A.;

Rotello, V. M. "ACS Nano 2014, 8, 10682-10686

27

And the strategy works for nanoclusters

• Membrane damage demonstrated by dye penetration

• ~50-fold less toxic to mammalian cells and RBCs

Xie, Y. Z. Y.; Liu, Y.; Yang, J. C.; Liu, Y.; Hu, F. P.; Zhu, K.;

Jiang, X. Y. Angew. Chem. 2018, 57 , 3958-3962.

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• With some efficacy in vivo, but no hemolysis data

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An even tougher challenge-biofilms!

• Biofilms are a fortress for bacteria…

• …that evolved over billions of years…

• …to protect against other bacteria (inc. antibiotics)

• Bacteria and extracellular polymeric substances (EPS)

• EPS includes proteins, glycans, nucleic acids…stuff

• MDR + biofilm = tough to kill!

29

Biofilm infections are hard to fight

• Wound biofilm infections are rapidly increasing with aging population

• Decreased immune capability, diabetes, obesity…

• Can sometimes be treated by injected antibiotics

• If not, then debridement (i.e. cut it out—ugh!)

• Often just untreated due to invasive treatment options

30

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• Cationic

• Neutral

• Anionic

• None of the above

What particle covering would penetrate biofilms best?

Audience Challenge QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

Reminder: biofilms are filled with bacteria, nucleic acids, negatively-charged glycans…

Cationic nanoparticles penetrate biofilms

• Anionic and neutral particles don’t

• As demonstrated using quantum dots

• What can we do with this info?.

Li, X. N.; Yeh, Y. C.; Giri, K.; Mout, R.; Landis, R. F.; Prakash, Y. S.;

Rotello, V. M. Chem. Commun. 2015, 51, 282-285.

32

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Nanoparticle-stabilized emulsions as antibiofilm agents

• Essential oils kill bacteria (another eons-long war)

• But they sit on top of biofilms

• Can we use the 150 nm particles to penetrate, oil to kill?

Duncan, B.; Li, X. N.; Landis, R. F.; Kim, S. T.; Gupta, A.; Wang, L. S.;

Ramanathan, R.; Tang, R.; Boerth, J. A.; Rotello, V. M. ACS Nano 2015, 9, 7775-7782.

33

The nanoparticles penetrate the biofilm

• Fluorescent SiONPs co-localize with bacteria

• But do the emulsions kill biofilm bacteria?

34

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Of course the emulsions kill the bacteria

• Not much of a story if they didn’t!

• And they take out MDR bacteria biofilms

• But lots of things kill bacteria...

• What about selectivity vs mammalian cells?

0 5 20 50 100

0

20

40

60

80

100

120

140

Via

bili

ty (

%)

Percentage of 2 % Emulsion Solution

CP-Cap

P-Cap

SiO2 NPs

Ppmt Oil

0 5 20 50 100

0

20

40

60

80

100

120

140

Via

bili

ty (

%)


CP-Cap

P-Cap

SiO2 NPs

Ppmt Oil

P. aeruginosa

CD-1006S. aureus

MRSA CD-489

35

The emulsions kill bacteria, help mammalian cells

• Fibroblast (healing) cells used to mimic wound

• Biofilm grown on top of fibroblast cells

• Bacteria wiped out—5 log unit reduction

• Fibroblast cells grow better—cinnamaldehyde is a growth factor

Via

bili

ty (

%)

Biofilm Log10

CFU

3T3 Cell Viability

0% 5% 20% 50% 100%

2

4

6

8


Bio

film

Log

10 C

FU

0

50

100

150

Tricky — bacteria are

presented in log scale,

mammalian cells linear!

36

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Other cationic hydrophobic systems also work

• MoS2 decorated with cationic chitosan and tetracycline

• System effective against S. Aureus and Salmonella biofilms

• Role of carrier components not entirely clear...

• ...but cationic seems to be the key

Xu, Z.; Wentao, Z.; Lizhi, L.; Mei, Y.; Lunjie, H.; Kai, C.; Rong, W.;

Baowei, Y.; Daohong, Z.; Jianlong, W. Nanotechnology 2017, 28,

225101.

37

Looking forward — combination therapies• Nanomaterials can work with traditional antibiotics

• AuNPs ‘plug’ efflux pump, restoring activity

• Additive is good, synergistic is better!

• Nano does nano, antibiotic provides specificity

• A new way to extend the life of current drugs?

38

Akash, G.; Neveen, M. S.; Riddha, D.; Ryan, F. L.;

Arafeh, B.; Khatereh, M.; Alexandre Rosa, C.; Kenneth, P.;

Morteza, M.; Rotello, V. M. Nano Futures 2017, 1, 015004.

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Nanoparticles provide new therapeutic strategies

-kill planktonic bacteria

-penetrate and destroy biofilms

-work synergistically with antibiotics

Plenty more to do, including...

39

The “Out of Time” Summary:

40

Some things to think about…

Improved therapeutic indices

In vivo testing

Testing in large animal models—mice ain’t us

Plus plenty of room for new materials and mechanisms!

25/04/2018

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42https://pubs.acs.org/journal/bcches

Journal Scope

Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecularconjugates.

25/04/2018

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43













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23

Celebrating 4 years & 40 Drug Discovery Webinars!http://bit.ly/acsDrugDiscoveryArchive

45

2014 2015 2016 2017

Chemical Entity and Biomolecule Scientific Program Tracks:

• Preclinical (including Discovery)• Bioanalytical• Clinical Pharmacology• Manufacturing & Bioprocessing• Formulation & Quality

YouTube video: https://www.youtube.com/watch?v=1DOxLBg0Ouw

Website: www.aapspharmsci360.org 46


http://www.aapspharmsci360.org/



25/04/2018

24

47Find out more about the ACS MEDI Division! www.acsmedchem.org

Join the Division Today!

For $25 ($10 for students), You Will Receive:

• A free digital copy of our annual medicinal chemistry review volume (over 600 pages, $160 retail price)

• Abstracts of MEDI programming at national meetings

• Access to student travel grants and fellowships

Be a featured fan on an upcoming webinar! Write to us @ [email protected] 48

“I attend frequently to the ACS Webinars on Drug Delivery Systems but I need to recognize that this particular webinar has been one of the best I have attended. Thank you for the efforts!”

How has benefited you?

Natalia Durán C., BSc. Pharmaceutical Biological Chemistry, National Autonomous University of Mexico

http://bit.ly/DDDS3video

25/04/2018

25

49



@AmerChemSociety


http://bit.ly/ACSwebinarsLI

50

Benefits of ACS Membership


Chemical & Engineering News (C&EN) The preeminent weekly digital and print news source.

NEW! ACS SciFinderACS Members receive 25 complimentary SciFinder® research activities per year.

NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.

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ACS Webinars does not endorse any products or services. The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the American Chemical Society.

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