Oral Presentation BacPath 13: Molecular Analysis of Bacterial Pathogens Conference 2015

Transcriptional response of methicillin-resistant Staphylococcus aureus (MRSA) to a novel polymyxin analogue (#35)

Jinxin Zhao 1 , Soon-ee Cheah 2 , Kade Roberts 2 , John Boyce 3 , Roger Nation 2 , Phil Thompson 2 , Zongjun Du 1 , Tony Velkov 2 , Matthew D. Johnson 2 , Jian Li 2
  1. College of Marine Science, Shandong University at Weihai, Weihai, China
  2. Monash University, Parkville, VIC, Australia
  3. Microbiology, Monash University, Clayton, VIC, Australia

Background: MRSA is currently one of the foremost multidrug-resistant pathogens. Polymyxins are cationic antimicrobial peptides (CAMPs) that were introduced over 50 years ago to treat Gram-negative bacterial infections. Although currently-available, polymyxins (B and E) are narrow-spectrum. We recently reported the synthesis of novel polymyxin analogues with activity against both Gram-negative and -positive pathogens. This study characterised the transcriptional response of MRSA to a polymyxin analogue (FADDI-019) that exhibits activity against Gram-positives.

Methods: The antimicrobial activity of FADDI-019 against MRSA strain ATCC 700699 was measured by time-kill analysis. In addition, we characterised the effect of FADDI-019 treatment on the MRSA cell wall by scanning electron microscopy (SEM). Finally, transcriptomics was used to monitor differential gene expression caused by sub-lethal levels of FADDI-019.

Results: Treatment of MRSA with FADDI-019 resulted in no bacterial regrowth within 24 h, indicating that MRSA was unable to develop resistance. SEM analysis showed that FADDI-019 treatment had no effect on cell morphology at concentrations up to 4×MIC. The MRSA transcriptome after FADDI-019 treatment revealed up-regulation of 112 genes and down-regulation of 85 genes. The transcriptomic data identified several cellular functions that were affected by FADDI-019 treatment, notably the vraSR two-component system, cell wall homeostasis (oppABCDF), amino acid metabolism, and virulence (saeRS). These findings were concordant with previous studies into the transcriptomic response of MRSA to three CAMPs. However, a number of additional cellular functions were affected specifically by FADDI-019 exposure including galactose metabolism, entertoxin expression (yent2, sei, sem, and seo), and infection.

Conclusions: We have shown for the first time that a novel polymyxin analogue is active against MRSA without the emergence of resistance. Our transcriptomics data reveal that FADDI-019 affects specific cellular functions in MRSA not affected by other CAMPs. Our study indicates that polymyxins can have different modes of action against Gram-negative and Gram-positive bacteria.