The differing biological fates of DNA minor groove-binding (MGB) antibiotics in Gram-negative and Gram-Positive bacteria.

"Antibiotics have been at the forefront of our fight against infectious disease since the 1940's. Since that time our reliance on antibiotics has been exposed by the rise of antibiotic resistant bacteria such as methicillin resistant Staphylococcus aureus (MRSA). Unfortunately, MRSA is not alone in its ability to resist the effects of antibiotics; other organisms such as Pseudomonas aeruginosa also have this ability. The World Health Organization considers solving the antibiotic resistance problem to be of global importance. One way of solving this problem is through the academic innovation of new antibiotic drugs to fight infectious disease.

We have been studying a group of compounds called MGBs that have very high activity against MRSA. Very little is known about the biological basis for this activity and we will determine the mode of action of these new drugs. We hypothesise that MGBs interfere with the ability of MRSA to control the use of its genes during infection. We will identify which genes are most potently inhibited by our new antibiotics providing us with a detailed set of targets. This information will be used in two ways. Firstly, knowledge of the targets of our drugs will help us to design new compounds that favour particular genes. Secondly, knowledge of the mode of action of a drug is important for gaining approval to use the drug in clinical trials and ultimately, the clinic.

Our previous research suggests that MGBs exhibit much better activity against organisms such as MRSA compared to Pseudomonas and E. coli. We hypothesise that this is because the latter two organisms are capable of expelling the MGBs from their cells using a system of pumps in the membrane. We will use cutting edge DNA sequencing technology to identify the resistance mechanisms of these bacteria and use this information to design new and better antibiotic MGBs to treat these infections in the future."

The differing biological fates of DNA minor groove-binding (MGB) antibiotics in Gram-negative and Gram-Positive bacteria.

"We have determined the transcriptomic effect of the antibiotic MGB-BP3 on S. aureus, allowing us to identify targets for further study into the mode of action of the antibiotic. We have confirmed the key findings of our RNA-Seq analysis using qRT-PCR and Biolog phenotype arrays, which matches the RNA-Seq findings.
We have just started work package two of the grant and we are establishing Tn-Seq with Pseudomonas aeruginosa to determine the mode of resistance in this organism."