SuperBugs Vs Michael McArthur

The village of Colney just outside Norwich City, in Norfolk England is home to the John Innes Centre (JIC), and the JIC is home to Dr. Michael McArthur and Professor Mervyn Bibb head of the JIC Department of Molecular Biology. Together they have achieved a possible solution to the rise in SuperBugs or super germs that are increasingly fatally resistant to current antibiotics. But not only that, as if that wasn’t good news enough the actual application could be the world’s first approved and consistently effective gene therapy. To understand the dual significance of this achievement it is necessary to know why the rising resistance of certain bacterium to antibiotics is a really big problem, and how Michael McArthur has come up with a probable resolution.

In 1947 just four years after Ernst Chain discovered how to isolate and concentrate penicillin for mass production, certain strains of the bacterium Staphylococcus aureus (Staph aureus or a Staph) were discovered to be resistant to penicillin. This marked Staph as a bacterium known to be highly adaptable and therefore resistant to antibiotics if exposed to them and subsequently surviving that exposure. The incidence of penicillin resistant staph infections now identified continued to rise and in 1950, 40% of hospital resident staph was found to be resistant to penicillin. By 1960 this had risen to 80% and developed one year earlier Methicillin was released by Beecham. This proved a successful treatment for just two years when Methicillin Resistant Staphylococcus aureus (MRSA) was identified in England in 1961.

Enter Vancomycin discovered by E.C. Kornfeld at Eli Lily, a global pharmaceutical company, within a soil sample from the depths of the Borneo jungles collected by a missionary. The so named Vancomycin was found to be produced by the Streptomyces orientalis bacterium contained within the Borneo jungle soil sample. With a growing rise in penicillin infections the FDA assisted Eli Lily and Vancomycin was approved for use in 1958. However though Vancomycin was potently effective against penicillin resistant staph it had a number of problems in its use and side effects.

Some of these effects like damage to the kidneys and hearing were caused by early manufacturing impurities, but others rare adverse effects like anaphylaxis, red man syndrome and superinfection still remain. This lead to Vancomycin being sidelined when Methicillin was approved shortly afterwards and which quickly grew to be the first line of defence when dealing with penicillin resistant staph. That is until 1960’s when MRSA bacterium took hold and now purer Vancomycin emerged from the shadows to become the last line of defence against MRSA.

Vancomycin together with its problems was however still thoroughly effective and it took nearly 35 years for MRSA to evolve a resistance to Vancomycin. In 1996 Vancomycin Resistant Staphylococcus aureus (VRSA also called GISA: Glycopeptide Intermediate Staphylococcus Aureus) or VISA: Vancomycin Insensitive Staphylococcus Aureus, but in general they are all referred to as MRSA), was identified in Japan and although its occurrence was rare, it signified the breaking of the last line of defence against MRSA. Luckily a new class of antibiotics featuring Linezolid was approved for use just four years later in 2000 which proved to be as effective as Vancomycin. It however only took MRSA just one year to break Linezolid with the first reported Linezolid Resistant Staphylococcus aureus (LRSA) resistance in 2001.

Which is about where we are six years later in mid 2007, and where are staph and its strains compared to our progress? Let see, there have been very few new approved antibiotic antibacterial treatments for MRSA. Of the ten treatments for MRSA of the prime three that can be used instead of Vancomycin or Linezolid; Daptomycin is for skin and skin structure infections only. Tigecycline was approved in 2005 but only for skin, soft tissue and intra abdominal infections. And only Quinupristin/dalfopristin derived from Pristinamycin seems somewhat effective internally. But along with the other ten there are enough various limitations and contra-indications that allow MRSA to slip though the treatment net and gain the fatal upper hand.

As an adversary in economic terms MRSA because of its adaptability and ability to break new antibiotics and render them useless (in market terms they would then no longer be the market share leader and therefore fall back behind more widely used first last defence treatments like vancomycin). As a result there has seen a significant drop in the funding of research and development of new antibiotics. Meanwhile as MRSA continues to spread and break down the existing effectiveness current antibiotics worldwide. There are no new approved replacements that can be widely used in various treatments of the different MRSA infections, as had been the case with penicillin, methicillin and to some degree vancomycin.

So at this point it’s about MRSA 5 points over 10 points of treatment not to bad you might say but now let’s look at the MRSA side of the comparison. Today worldwide, a conservative estimate of 2 billion people are infected with Staphylococcus Aureus, that means roughly 1 out of every 33 people you encounter will be infected if not yourself. Of these 2 billion infected people 53 million of them are estimated to carry the MRSA strains. In three US communities a population review showed that 18-25 people out of every 100,000 people were staph infected and of those 2.5 million had MRSA infections. It took Staphylococcus Aureus 4 years to break penicillin, 14 years for methicillin and 35 years for vancomycin but only 1 year for linezolid and no significant long term replacements since. Staphylococcus Aureus is also now a permanent resident in the majority of hospitals worldwide with MRCA strains climbing hard on its heels for the same status. That’s about another 10 point to MRSA and climbing, a bleak picture indeed, but then along comes Michael McArthur, the JIC and Streptomyces, the largest genus of Actinobacteria.

The Streptomyces Genus contains over 516 known species alone, and accounts for over two thirds of today’s medically useful antibiotics of natural origin. This includes Streptomycin (from S. griseus), Tetracycline (from S. rimosus), Vancomycin (from S. orientalis), and Rifamycin (from S. mediterranei) amongst others. This most useful Genus has become one of the most comprehensively studied Geneses of the Bacterial Kingdom. But in 2000 JIC in conjunction with Sanger Centre and funded by the BBSRC and the Beowulf Genomics initiative of the Wellcome Trust. Chose to take this study much deeper and to sequence the entire DNA Genome of Streptomyces coelicolor strain A3(2). This was completed two years later and the staggering amount of information was then utilised at JIC as a base from which to further studies.

“In the Department of Molecular Microbiology we study bacterial metabolism, physiology, gene regulation and development, and plant-bacterial interactions.”-Professor Mervyn Bibb

Headed by Professor Mervyn Bibb, his department opened up five lines of study using the S. coelicolor genome sequence in 2002.

“The Department's comprehensive Streptomyces programme, studying antibiotic production, morphological differentiation and stress responses, is underpinned by the newly-acquired genome sequence of the model species S. coelicolor, and cutting-edge techniques in functional genomics.”-Professor Mervyn Bibb

Enter new contender Dr. Michael McArthur, with 15 MRCA - 10 Treatments, who together with Bibb and his team in just five years using the S. coelicolor sequence took a completely different direction to the normal method of antibiotic development yet one that could prove effective. In December 2007 they announced a radical new form of MRSA treatment.

“We are putting genetic information directly into drugs. This is the first application of a DNA based therapy”-Dr. Michael McArthur

JIC has developed a highly efficient targeted gene disruption procedure that involves taking a short stretch of DNA and delivering it within an existing antibiotic that targets the bacterial infection. Once delivered the piece of DNA acts as a Decoy within the bacterial cells.

“The DNA sequence acts as a decoy, disrupting gene expression and blocking resistance”-Dr Michael McArthur

Unable to express the required DNA for the specific resistance to the antibiotic used as the carrier the bacterium then succumbs to the antibiotic. This heralds a whole new possible approach to the treatment of the MRSA worldwide epidemic.

“Natural resistance will always be hot on the heels of a new antibiotic because they co-evolve. Ours is not a traditional pharmaceutical approach and provides a completely new challenge to bacteria”- Dr Michael McArthur

So before the JIT discovery we were developing new antibiotics in the hope that each one would last long enough so that when staph does develop resistance to it, another one could take its place. A process that has been somewhat decimated by staph’s adaptability and is looking more futile everyday. Staph apart from being rather tenacious has for the most part built resistances from incorrect antibiotic prescription and misuse since penicillin was first mass produced. If decoys can stop the very DNA expression process that staph uses to defend itself against current antibiotics then we have for the first time an opportunity wholly prevent the survival of staph infections within the body either as a carrier or afflicted. This means that staph will not only will become susceptible to existing antibiotics but also future ones. The cycle of staph’s adaptation, survival and consequent spreading of MRSA resistant strains should be halted, in its tracks so to speak.

Sometimes one great discovery leads to another and as promising and successful their first tests with selected decoy DNA was Dr Michael McArthur faced with the problem of how to find the right Decoy DNA within a whole gene strand. This lead to process being discovered that does not require specific knowledge of the whole gene from which the decoys are snipped. This process they have patented under a new company called Procarta Biosytems Limited formed by The John Innes Centre, Plant Bioscience Limited (PBL) and the founding scientists Dr Michael McArthur and Professor Mervyn Bibb. It all sounds very promising and if Procarta get their new approach approved for use then it would see MRSA down to 0 and 11 points for Treatments. This coming at a time when we really do need a new successful treatment because unless Procarta, with its decoys and new processes can turn the tide, MRSA is winning hands down and gaining ground everyday.

Though it doesn’t stop there, as Procarta has its sights set on more than antibiotic decoys and is looking at industrial applications for their discoveries within the genome of Streptomyces coelicolor strain A3(2).

“Streptomyces is the enzyme producing bacterium with bells and whistles, set to make a major contribution to a market already predicted to be worth £400 million by 2010…By using bacteria, many industrial processes could be cleaned up”-Dr Michael McArthur.

For not only is Streptomyces a virtual powerhouse producing significantly high yields of enzymes and proteins. It also can secrete these substances through its cell walls and be thereby be harvested without extraction from the Streptomyces themselves in what would be a destructive and costly process. This means Streptomyces has a great potential in the new White biotechnology industry which seeks to use bacteria to replace conventional industrial processes. Most of today’s conventional industries used to produce important medical and commercial chemical compounds are environmentally harsh and unsustainable. They employ a range of hazardous petro-chemicals, high temperatures and result in many toxic by-products. White biotechnology on the other hand is defined by using bacterium in a bacterial process, which is a clean renewable and therefore sustainable. It generally has little or no impact on the environment and its by-products can be carefully controlled if not eliminated or re-used. If Procarta is as successful in this direction as they seem to be so far with decoys in antibiotics, it could see a whole new range of white biotechnologies taking over from conventional industry technologies.

So from whichever way you look at it Dr Michael McArthur is a new contender not only for the perhaps the greatest shift in medicine since Fleming and Chain and the first opportunity to truly climb into the ring with MRSA and have the chance at a permanent knockout. But also in the quest to rapidly replace as many unsustainable, environmentally unfriendly and petro-chemical dependant industrial processes as possible, in the looming shadows of Global Warming and Peak Oil.

This article was written By Ivor W. Hartmann at The IWH Inquirer.