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Welcome to our blog! We are the Merrill Antimicrobial Research Group, based out of the University of Guelph in Guelph, Ontario, Canada.

Interested in learning more about the future of antibiotic resistance, and what we are doing to help?

Antibiotic resistance is a topic that affects us all – but did you know it was such a growing concern? A battle we are slowly starting to lose?

More importantly, did you know that there is an alternative strategy (we’re working on it!) in the war against bacteria, beyond traditional antibiotics?

Let us introduce you to a new term:

ANTIVIRULENCE COMPOUNDS

And let us start from the beginning…

One of the most significant challenges facing modern medicine is antibiotic resistance. For over 60 years antibiotics have been our weapon of choice in the fight against disease, significantly reducing deaths caused by common infections such as meningitis, strep throat and pneumonia. Despite these victories, bacteria are fighting back and have now developed resistant strains to every antibiotic that has been produced. The CDC estimates that 2 million people in the USA each year are infected with resistant bacteria, directly resulting in 23,000 deaths. This does not include deaths from complications that were potentially made worse due to a resistant infection. Resistance can rapidly spread between bacteria and is a global phenomenon.

We cannot look to pharmaceutical companies for a solution to this problem it is not a good business model for them. The last new class of anti-bacterial drugs were discovered in the 1980’s. Financially, antibiotics do not make for a good investment for several reasons. Antibiotics are only used for a few weeks and then the patient should be cured, whereas a drug to treat a chronic illness (antipsychotics, for example) is used over an extended time, perhaps even a lifetime. As a result of multi-drug resistance, the life span of antibiotics is short and it must be discontinued after a few years. It costs between 600 – 800 million dollars and 12 years to get a drug approved for human consumption. With traditional suppliers of medicine out of the game, this leaves production of new drugs to governments (who are not very proactive with research spending) and Universities.

Antibiotics place tremendous selection pressure on bacteria, forcing them to adapt. Therefore, resistance is a natural and inevitable outcome of using these treatments. Antivirulence compounds “disarm” bacteria of their biological weaponry by binding to their virulence factors (weapons of war in disease) and jamming their chambers. This disables their ability to damage our cells. Our lab has designed inhibitors (drugs) that bind to the bacterial factors and prevent them from working properly. We’ve worked with dozens of bacterial toxins, from several organisms including Salmonella, V. cholera, E. coli, and Listeria.

Our research group has been studying the family of bacterial virulence factors known as the mono-ADP-ribosyltransferases (mARTs) since 1991. During the past 10 years, we have developed some effective inhibitors against this class of bacterial toxins, many of which participate in infections and diseases caused by bacterial pathogens. Remarkably, we have found a suite of compounds that are effective against a wide array of bacterial toxins and these agents may function as `broad spectrum` compounds against human, animal and plant pathogens. We have recently shown that some of these agents are effective inhibitors against LMO toxin produced by the food borne pathogen, Listeria monocytogenes. We filed a US patent (Jun 2012) #13/310,051 on antivirulence compounds inhibiting bacterial toxins.

Antivirulence drugs are compounds that disarm bacteria without killing them, thereby allowing the infected host to use its normal immune system defenses to control or remove the infection. Antivirulence drugs are considered the next viable strategy believed to treat bacterial infections while avoiding the development of antimicrobial resistance (AMR) to the treatment (drug). In general, scientists and pharmaceutical companies are losing the race to develop new antimicrobial drugs faster than pathogens can develop antimicrobial resistance. Currently, every antibiotic ever used, has a corresponding bacteria that has developed resistance.

As we run out of solutions (new drugs) to treat a growing number of resistant pathogens, we must stop the cycle of creating superbugs by using methods which do not stimulate pathogens to develop AMR. Drugs that neutralize or inhibit the toxins (virulence factors) produced by pathogens is one such method, which does not favour the survival of one bacteria over another, therefore does not stimulate them to mutate in order to survive.
Traditional antibiotics aim to kill (bacteriocidal) or stop the growth (bacteriostatic) of pathogens, but antivirulence drugs prevent disease by neutralizing the bacteria’s weapons the bacteria use to cause damage during an infection. Traditional antibiotics target functions essential to bacterial survival which places tremendous selective pressure on the bacteria to evolve into a new resistant strain.

Antivirulence drugs target the specific virulence factors essential to establish damage and disease, such as toxin function, toxin delivery, quorum sensing ability, multi-step cell regulatory systems, virulence gene regulation, or cell adhesion. The benefits of this approach are 2-fold: reduction in selective pressure for resistance and equally important preservation of the host’s microflora.

Currently, no antivirulence drugs have been approved for human use, but many are in development, however, the industrial pipeline of novel antibacterial drugs is presently empty.

Industry and academics now accept that there is no “one-drug-fits-all” strategy and that pathogens will need to be attacked based on their specific virulence factors using multiple effectors and not on a single broad based mechanism as has been done in the past with traditional antibiotics.

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