Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2014

Investigations into the Biological Mode of Action of Novel Antibacterial Compounds (#348)

Nikki Y. T. Man 1 , Scott G. Stewart 1 , Allan J. McKinley 1 , Thomas V. Riley 1 , Katherine A. Hammer 1
  1. University of Western Australia, Crawley, WA, Australia

A major public health problem that our society is currently facing is the growing trend in antimicrobial resistance. Due to increasing antimicrobial resistance, the number of currently available antimicrobial treatment choices for more serious bacterial infections is steadily decreasing.1 

Medicinal chemistry studies of a promising compound discovered by the Stewart/McKinley group lead to compound 135C. It is found to exhibit antimicrobial in vitro activity against many Gram-positive bacteria, including MRSA and Clostridium difficile, at concentrations comparable to those required for existing drugs.2 

  The main aim of this project is to establish a pharmacological study for 135C, defining parameters such as susceptibility to pathogenic organisms, its structure-activity relationship and its mechanism of action.

Susceptibility tests were conducted to determine the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of 135C against a variety of pathogenic organisms. The compound was found to be active against Gram-positive bacteria with MIC values ranging from 0.12 – 0.5 μg/mL for MRSA, and an MBC value of >32 μg/mL. Given the large difference between the MIC and MBS, its activity is deemed bacteriostatic.

Time-kill studies showed that S. aureus exposed to 32 μg/mL of 135C did not die over the 4 hr time period, indicating a relatively slow effect and no cell leakage. Experiments investigating whether 135C caused cell lysis gave a negative result as bacterial cell contents were not detected. These experiments have shown that the bacterial cell wall is not the main target of 135C.

  1. Daniela Jabes, The antibiotic R&D pipeline: an update, Current Opinion in Microbiology, Volume 14, Issue 5, October 2011, Pages 564-569, ISSN 1369-5274, http://dx.doi.org/10.1016/j.mib.2011.08.002. (http://www.sciencedirect.com/science/article/pii/S1369527411001330)
  2. Boulos, R. A., Man, N. Y., Lengkeek, N. A., Hammer, K. A., Foster, N. F., Stemberger, N. A., ... & Stewart, S. G. (2013). Inspiration from Old Dyes: Tris (stilbene) Compounds as Potent Gram‐Positive Antibacterial Agents. Chemistry-A European Journal, 19(52), 17980-17988.