Saturday, January 15, 2011

Methicillin-resistant S. aureus (MRSA) JKD6229, freaking out and deadly

Stringent response, as I wrote here, here, and here, and here, is a central regulator of bacterial physiology, which decides whether to grow happily churning out new proteins without a care or to shut down all of the unnecessary systems, relocate all  resources to amino acid production and put up a fight. So what happens if a mutation hyper-activates it in Staphylococcus aureus? Wonder no more - the pathogen goes berserk!

The strain in question is called JKD6229 and it was reported in the resent paper by Gao at al. in PloS Pathogens. It was discovered among the clinical isolates, and rigorous analysis showed that it has continuously activated stringent response with elevated levels of ppGpp alarmone. Previous studies implicated stringent response in bacterial virulence, demonstrating that inhibition of this mechanism renders bacteria inapt for any sort of shenanigans (for review see Dalebroux et al. 2010).

Digging deeper, authors discovered that JKD6229 had a whole set of mutations making it nasty.

First was a set of mutations rendering it resistant to several antibiotics. Modified topoisomerase IV gave it resistance to cyproflaxacin, RNA polymerase was altered to give it resistance to rifampin and ribosomal large subunit methyltransferase RlmN had an insertion making it insensitive to linezolid. It short - this bug was really, really hard to kill. 

Second, authors report that the bug had mutated RelA, which had low activity in ppGpp hydrolysis, leading to accumulation of high ppGpp levels. High ppGpp level inhibits ribosome synthesis and results in slow growth, so the strain was dubbed as "Small Colony Variant". At the very same time, all the defense mechanisms were on high alert, and JKD6229 was not expecting anything good from the world around it. It was not growing fast, but it was hard to kill and it was fighting back. 

One very, very pissed off bacterium. 

And there are several ways to deal with it.

First, you can kill it (see my earlier account on the development of antibacterials). Surely, JKD6229 will be trying hard to survive, accumulating even more resistance markers.

Second, you can try calm it down, make it non-virulent. This approach is an emerging strategy in development of antibacterials - inhibiting virulence, but not killing the bug. There are two potential benefits. First, lower selective pressure for resistance mutants since in most of the tissues virulence is not needed for survival. Second, potentially higher selectivity - only the bad bugs perish, and the good ones live. However, there are problems with this approach. Virulence mechanisms are very diverse, and therefore drugs targeting them will have a very narrow spectrum. And usually you do not know exactly what sort of bug is causing the problem. Development of rapid diagnostic methods can fix this, and then 'narrow spectrum' becomes 'selectivity', and this is a good thing.

PS: Wait! Mutations in Staphylococcus aureus RelA? Well, surely not. Staphylococcus aureus does not have RelA. The protein authors refere to is Rel, a bi-functional protein capable of both producing and hydrolyzing ppGpp, as opposed of RelA, which is able only of ppGpp syntheses. For more information on phylogenetic relationships between RelA, Rel and SpoT see Mittenhuber 2001.


Gao W, Chua K, Davies JK, Newton HJ, Seemann T, Harrison PF, Holmes NE, Rhee HW, Hong JI, Hartland EL, Stinear TP, & Howden BP (2010). Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infection. PLoS pathogens, 6 (6) PMID: 20548948

Dalebroux ZD, Svensson SL, Gaynor EC, & Swanson MS (2010). ppGpp conjures bacterial virulence. Microbiology and molecular biology reviews : MMBR, 74 (2), 171-99 PMID: 20508246

Mittenhuber G (2001). Comparative genomics and evolution of genes encoding bacterial (p)ppGpp synthetases/hydrolases (the Rel, RelA and SpoT proteins). Journal of molecular microbiology and biotechnology, 3 (4), 585-600 PMID: 11545276

Escaich S (2010). Novel agents to inhibit microbial virulence and pathogenicity. Expert opinion on therapeutic patents, 20 (10), 1401-18 PMID: 20718591

Mendeley group on stringent response

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