University of Illinois at Chicago College of Pharmacy UIC

Background Chemical Structures of Compounds

Conclusions and Future Directions

Hypothesis

Traditional antibiotics kill bacterial pathogen or inhibit bacterial

growth by blocking the synthesis of cell wall, proteins and nucleic

acids. However, due to the emergence of multi-drug resistant

bacteria, current antibiotics, either as a stand-alone treatment or

in combination, are met with only partial success. Therapeutic

strategies targeted to combat the creeping rise in intrinsic

antibacterial resistance are further attenuated by acquired

resistance via additional mechanisms such as target mutations,

increased expression levels of efflux pumps and antibiotic-

degrading enzymes. As community-acquired pathogens are

exhibiting increasing levels of resistance to current antibiotics,

medicinal chemistry-based drug discovery efforts are aimed to

design alternative molecular scaffolds to target antibacterial

growth and acquired resistance.

Discovery of a Novel Class of Potent, Broad-Spectrum Antibacterial Agents Containing

Oligoamines Attached to Bis-Ureas or Bis-Thioureas

Boobalan Pachaiyappan1,* Bo Wang2, Yong-Mei Zhang2, Patrick M. Woster1

Contact Information: (1) Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States; (2) Department of Biochemistry and Molecular Biology, Medical University of South

Carolina, Charleston, SC 29425. *Email: pachaiya@musc.edu

Experimental Design Preliminary Screening Results

Antibacterial Profile of BP-107-5

BP-107-5 emerged as a lead compound with favorable

antibacterial profile. Further studies, including optimization of BP-

107-5, is an ongoing pursuit in our Laboratories

Substituted oligoamines and their isosteres can be developed as

potent broad-spectrum antimicrobial agents to treat both wild-type

and multidrug resistant Pseudomonas aeruginosa (Pa),

Staphylococcus aureus (Sa) and Escherichia Coli (Ec)

• Synthesize oligoamines of various linker sizes

• Characterization using NMR and MS

Organic Synthesis

• MIC against Pa, Sa and Ec

• Selectivity

Preliminary Screening

• MRSA studies

• Time-kill kinetics

• Mechanism

• Biofilm studies

Pharmacological Profile

Acknowledgements

• NIH 1-RO1-CA149095

(PMW)

•DOD Grant DM090161 (YMZ)

•SCTR High Innovation-High

Rewards Pilot Project (UL1

RR029882)

• Shiv K. Sharma

• Jordon D. Gruber

• Hubert H. Attaway

• Sarah E. Fairey

• Michael Schmidt

• Nancy M. Smythe

• MIC values of active compounds range between 2 to 256 µg/ml

• Bis-aryls are more active compared to the mono-aryl counterparts

• Most potent compounds are 5 (3-4-3), 14 (3-5-3), 16 (3-6-3) or

verlindamycin

• Isosteres 19-21 (without central amines) displayed no activity

• BP-107-5 (MIC 2 µg/ml) has greater antibacterial activity than

gentamycin (MIC 8 µg/ml) or chloramphenicol (MIC 8 µg/ml)

• Natural polyamines spermine (MIC >256 µg/ml) and spermidine

(MIC >256 µg/ml) are inactive under test concentrations

Isolate ID SPA type

MIC50

(g/ml)

10082 B 1 1

10076 B 2 1

30253 CA 7 2

20225 B 15 2

20467 BA 59 2

BP-107-5 is highly

effective against five

MRSA clinical isolates

In time-kill kinetics

(10 X MIC) assay, BP-

107-5 killed 99% Sa and

Pa bacteria in 3 hours

BP-107-5 causes Sa

membrane disruption

resulting in nucleic acid

and protein release

BP-107-5 inhibits

biofilm growth

and promotes

biofilms

dispersal

Transmission Electron

Microscope Imaging shows BP-

107-5 (2XMIC, 15 mins) treated

Pa causes disruption in cells

and membranes Selectivity Profile of BP-107-5

CC50

(g/ml)

MIC50

(g/ml)

Selective Index

(CC50 /MIC50)

S. aureus 32 1 32

P. aeruginosa 32 6 5.3

E. coli 32 1 32

Cell proliferation

assay (MTS

method, 293T

human kidney

cells)

control BP-107-5 treated Pa