News & Events
Approaches to new antibiotics acting via novel mechanisms
Speaker(s): Dr Michael J. Kelso
When: 28 September 2015 (2pm)
Where: SBS Classroom 2 ( SBS-01-22, Level 1)
Type: Seminars

The seminar will describe results from three projects in the Kelso Lab aimed at discovering new antibiotics that exert their effects through novel biochemical mechanisms. The first part of the talk will highlight our program exploring new agents for use in antimicrobial photodynamic therapy (aPDT), where photosensitisers and visible light are used to generate phototoxic species that kill bacteria. We are exploring a novel class of hybrid compounds that combine the photosensitiser methylene blue with inhibitors of microbial efflux pumps. The second project uses fragment-based screening methods in combination with X-ray crystallography to generate potent inhibitors of the bacterial b-sliding clamp, a novel antibacterial target that plays a central role in bacterial DNA replication and repair. This work is being carried out in collaboration with A/Prof Aaron Oakley/Prof Nick Dixon (UoW) and Prof Elizabeth Harry (UTS).1-3

The second part of the talk will highlight results in the area of NO-donor antibiotics as biofilm dispersing agents for the treatment of chronic bacterial infections. Low concentrations of nitric oxide (NO) was shown by collaborators (A/Prof Scott Rice, Prof Staffan Kjelleberg and Dr Nicolas Barraud) to act as a signal that induces bacteria in biofilms to disperse and revert to the free-swimming (planktonic) form. This discovery unveiled an exciting new anti-biofilm paradigm; use of NO-releasing compounds in combination with antibiotics to clear biofilm infections, as it is well established that planktonic bacteria are up to 1000 times more susceptible to antibiotics and host immune defenses than their better-protected biofilm counterparts. We have designed, synthesized and provided in vitro proof-of-concept validation for cephalosporin-based NO-donor prodrugs (DEA-CPs) that provide biofilm-targeted delivery of NO via the mechanism shown below. The targeted NO signal induces bacteria in biofilms to disperse and when used in combination with antibiotics DEA-CPs are able to effectively kill biofilm pathogens.[4,5]

References

(1)        Yin, Z., Whittell, L. R., Wang, Y., Jergic, S., Ma, C., Lewis, P. J., Dixon, N. E., Beck, J. L., Kelso, M. J., Oakley, A. J. (2015). “Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs.” J. Med. Chem. 58, 4693-4702.

(2)        Yin, Z., Wang, Y., Whittell, L. R., Jergic, S., Liu, M., Harry, E. J., Dixon, N. E., Beck, J. L., Kelso, M. J., Beck, J. L., Oakley, A. J. (2014). “DNA Replication is the Target for the Antibacterial Effects of Non-Steroidal Anti-Inflammatory Drugs.” Chem. Biol. 21, 481-487.

(3)        Yin, Z., Whittell, L. R., Wang, Y., Jergic, S., Liu, M., Harry, E. J., Dixon, N. E., Beck, J. L., Kelso, M. J., Oakley, A. J. (2014). “Discovery of Lead Antibacterials Targeting the E. coli Sliding Clamp using a Fragment-Based Approach.” J. Med. Chem. 57, 2799-2806.

(4)        Yepuri, N. R., Barraud, N., Kardak, B. G., Kjelleberg, S., Rice, S. A., Kelso, M. J. (2013).  “Synthesis of Cephalosporin-3′-Diazeniumdiolates  ? A new class of biofilm dispersing NO-donor prodrugs activated by β-Lactamase.” Chem. Comm. 49, 4791-4793.

(5)        Barraud, N., Kardak, B. G., Yepuri, N. R., Howlin, R. P., Webb, J. S., Faust, S. N., Kjelleberg, S., Rice, S. A., Kelso, M. J. (2012). “Cephalosporin-3’-diazeniumdiolates as targeted NO-donor prodrugs for dispersing bacterial biofilms. Angewandte Chem. Int. Ed., 51, 9057-9060.