Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance

The Antibiotic Perfect Storm

Shifting the paradigm of antibiotic discovery and development
5/26/2012 Bacteriotix - Science Shaping our World 1

The antibiotic and resistance
pipelines converge

Clatworthy, et al. 2007. Nature Chemical Biology 3, 541 – 548.


Why no new drugs?
• Resistance rapidly emerges and spreads, limiting
antibiotic shelf-life and returns on investment
• Limited duration of antibiotic use results in lower
returns on investment

• The price paid by consumers does not reflect the
relative effectiveness of the drug, i.e. it saves lives!

• Targeting new antibiotic mechanisms represents
significant risk to investors

Medically relevant bacteria

Gram-positives Gram-negatives
Staphylococcus Pseudomonas
Streptococcus Neisseria
Corynebacter Legionella
Listeria Haemophilus
Bacillus Klebsiella
Clostridia… Escherichia
Salmonella
Helicobacter
Proteus
Enterobacter
Serratia…

Very few lineages to target

Humans as microbial fermenter

9 of every 10 cells in the human body are microbial
few are ever pathogenic

Microbes-R-Us

Most contribute positively to human health or are
even required for life

Current approach to treating infectious
disease
Toxicity
Resistance
Allergic reactions
Immune suppression
Destruction of beneficial gut flora
Overgrowth of pathogens
And - they are less effective over time

H bomb explosion on Marshall Islands, 1952

Broad spectrum antibiotics
decimate normal, healthy microbial community

Few lineages make or use antibiotics

Eucaryotic molds
(Pencillium and Cephalosporium)

Two types of spore-forming
bacteria
(Actinomycetes and Bacillus)


Most pathogens live in biofilms

Naturally resistant to antibiotics

Use of Broad Spectrum Antibiotics
– Ecologically unsound
• uncommon in natural populations
– Selects for massive resistance
• target populations are immense
– Maintains resistance
• selection for resistance is maintained
• resistance costs are ameliorated
– Ineffective against many pathogens
• High levels of resistance
• Can’t penetrate biofilms
– Devastates the healthy flora
• opens door to opportunistic pathogens


Think outside the box

How would bacteria solve this problem?

Bacteriotix
Employing ecologically sound approaches
to meet the challenges of antibiotic resistance

The guided missile approach

Most bacteria employ narrow spectrum toxins to fend off
invaders or competitors

- kill their closest relatives -

Bacteriocins
the microbial weapon of choice

• All Archeae
• All Bacteria
• Many/most microbial
Eucarya

• Common bacteriocins
– Colicins
– Nisin
– Pediocin
– Pyocins
– Lacticin

Easy to find

Bacteriocin structure and function

Kleanthous (2010) Mol. Microbiol 75, 529

The true “designer” drug

Zouhir, et al. 2010. A new structure-based classification of Gram-positive bacteriocins.
Protein J., 29: 432-439.

How narrow is narrow-spectrum?

Riley et al. 2005. JME 54: 210-218


Bacteriocins
Long history of use in food preservation
FDA - GRAS


New interest in bacteriocin use in
human health
• MIC’s comparable to antibiotics


As effective as antibiotics
100

90

80

70
Inhibitory Percentage

60

50

40

30

20

10

0
am sam δ cip E4 sxt β α E9 H cz γ fox ft gm
Bacteriocin/ Antibiotic

400 uropathogenic strains of E. coli – comparable or lower MIC’s
Riley et al, unpublished

human health
• Act in synergy with antibiotics


Effective in combination therapies

Kiri et al. 2002. Combinations of lysostaphin with beta-lactams are synergistic against
oxacillan-resistance Staphylococcus epidermis. AAC 46: 2017-2020.


human health
• Breaks down biofilms


Effective in biofilms

Smith et al., 2012. Activity of Pyocin S2 against Pseudomonas aeruginosa
Biofilms. AAC 56(3):1599.

Effective in biofilms

Nel et al. 2002.Effect of bacteriocin pediocin PD-1, plantaricin 423, and nisin on biofilms
of Oenococcus oeni on a stainless steel surface. Am. J. Enol. Vitic. 53: 191-197.


human health
• Effective in vivo


In vivo activity in renal infections

Dixon et al. 1968. Lystostaphin: an enzymatic approach to
staphylococcal disease. JBM. 41: 62-69.

In vivo activity in aortic valve infections

Patron et al. 1999. Lysostaphin treatment of experimental aortic valve endocarditis
caused by a Staphylococcus aureus isolated with reduced susceptibility to vancomycin.
AAC 43: 1754-1755.


In vivo activity in liver infections

Ingham et al., 2003. The bacteriocin piscicolin 126 retains antilisterial activity
in vivo. JAC 51: 1365-1371.

human health
• Effective in vivo
• Reduced selection pressures for resistance


Resistance mutation rates
Mutation rate
the number of mutation events per gene per unit of time
Broad spectrum antibiotics is ~1 x 10-6
Bacteriocins: roughly the same rate

Mutational targets
Broad spectrum antibiotics is >>1012
Bacteriocins is minimal, <<106


Resistance is costly

Dykes et al. 2002. Fitness costs associated with class IIa bacteriocin resistance in Listeria
moncytogenes. LAM 26: 5-8.

Resistance can be delayed

Riley et al., Unpublished

Colicin cocktail creation



Bacteriocin advantages
• Easy to find
• Highly specific
• Low MIC’s
• Long history of use in food preservation – GRAS status
• Active in vivo (in animal blood, liver and kidney, human
serum, oral cavity, intestine, urinary tract infections)
• Active against non-dividing and dividing cells and biofilms
• Little to no toxicity to human cells, no immune reaction
• Ease of genetic manipulation and production
• Reduced resistance levels and high cost of resistance


Bacteriotix, LLC
Product pipeline
• Urinary tract infections
• In-dwelling urethral catheters
• Superficial skin infections
• Lung infections of patients with cystic fibrosis


Effective in catheters

Trautner et al. 2005. Colicins prevent colonization of catheters. JAC 56:413-415.

Colicins effective in UTI’s in vivo


Superficial skin and burn infections

DOD interested in developing
bacteriocin-based gel for
battlefield use against SSI’s

Also interested in using them to limit
density of pathogens in warfighters
local environment – attaching
bacteriocins to the surfaces of
cots, tents, uniforms, etc.


Comments on creating a company
• The good Turning basic science into applied,
Potentially saving lives,
Return on taxpayer’s investment,
Perhaps creating a nice retirement fund…

• The bad Entirely new approach – not in Kansas anymore,
Raising capital – worse than grant-writing – if
that is possible,
Dealing with investors – I wouldn’t know yet – am
open for that experience…

• The ugly….. I already have a day-job!


Rob Dorit
Smith College

Sandy Robinson
Chris Roy Danielle Fedora
Suphan Bakal Institute For Drug Resistance
Jenna Farrell
Shanika Collins

Bacteriotix Partners & Collaborators

Institute for Drug Resistance

New Gordon Conference on Drug Resistance
AAM colloquium on drug resistance
Over 4,000 members in 2 years

Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance

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Science Shaping Our World-SHOW: Resistance is Futile: Applying Ecological and Evolutionary Theory to the Challenge of Antibiotic Resistance