The World Health Organization has identified antimicrobial resistance as a serious risk to global health. In a recent study, a new antimicrobial was able to cure mice infected with bacteria that was believed to be almost “untreatable” in humans. Furthermore, resistance to the drug was virtually undetectable.
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Over time, bacterial resistance to antibiotics only increases. The problem is further aggravated by the fact that the current pharmaceutical industry model lacks certain incentives to discover and develop new antibiotics.
Bringing a drug to market involves billions of dollars in expenditures, with additional years required to recover that investment.
In terms of return on investment (ROI), intermittent 10-day prescriptions cannot compete with lifelong treatments for conditions like blood pressure and cholesterol management. Consequently, only one new class of antibiotics has been developed since the year 2000, and there are only a few new candidates on the horizon.
In this episode, Mike Mahan, Professor in the Department of Molecular, Cellular and Developmental Biology at UC Santa Barbara, offers some key insights regarding the following:
- The challenges of developing new antibiotics and the need for new business models or societal incentives to fund them.
- A supplement to the gold standard test for susceptibility that can lead to better patient outcomes.
- A promising candidate for a new class of broad-spectrum antimicrobials for which resistance is almost undetectable.
Addressing the issue of antibiotic resistance requires considerable effort on multiple fronts. As a society, there is a need to acknowledge the seriousness of the problem and make a conscious decision to invest in the development of new drugs and models that can facilitate future development.
For instance, consider a subscription model where companies are compensated for developing new kinds of antibiotics, regardless of whether they are used.
Improved Predictive Susceptibility Test
First of all, there is the question of whether antibiotics are being used in ways that maximize their benefits. The standard test for antibiotic susceptibility typically takes place in ‘rich media,’ which are optimal conditions for bacterial growth. However, what if the test conditions were altered to more closely resemble in vivo environments? Would we observe the same results under these more realistic conditions?
Mahan and his colleagues designed and conducted a study comparing the results of susceptibility tests performed using either rich or minimal growth media, the latter more closely resembling the host environment. Furthermore, they demonstrated the effectiveness of a new antibiotic in treating sepsis in mice.
Although there was a discrepancy in ten percent of the cases between the standard benchmark test and the new minimal growth test regarding the clinical threshold, it led the team to question whether the bacteria were truly resistant or simply less susceptible.
Mahan explains, “Using this test, we now check FDA-approved antibiotics that are dismissed by the gold standard test… there were several antibiotics that were highly effective in treating sepsis in mice that are never used by physicians because the gold standard test says it won’t work. Consequently, our toolbox for antimicrobial infections is much larger than we once thought.”
A Promising New Class of Antimicrobial
In a separate investigation carried out by one of Mahan’s colleagues, conjugated oligoelectrolytes (COEs) were under scrutiny for their potential for charging cellphones on the battlefield - a bacterial battery, so to say.
Using bacteria as an energy source to propel the electron transport process, it came as no surprise that driving electrons out of the cell for this application, rather than inwards, damages the bacteria in the long run. This led to the hypothesis that COEs could be potential candidates as new antibiotics.
Initially, Mahan was skeptical, likening the compounds to bleach—effective for killing bacteria but highly toxic for humans. “This is going to be a really short collaboration,” he said to his lab manager.
After testing 17 different COE compounds for antimicrobial activity and toxicity in mammalian cells, they were able to demonstrate that all 17 had no problem killing bacteria. While the majority of them were indeed extremely toxic for mammalian cells, as predicted, one of the 17, COE2-2hexyl, displayed promise as it was deemed less toxic for mammalian cells.
Subsequently, the team immediately tested this compound for its efficacy in curing sepsis in mice. Mice were infected with a series of various pathogens, including an isolate from a patient that had succumbed to refractory bacteremia, a multiply-resistant strain of Klebsiella from a community-derived urinary tract infection.
The researchers assessed the toxicity of the compound in mice by using blinded measurements of attitude scores, which included appearance, activity, and clinical signs following drug treatment. The results showed that the compound was well tolerated by the mice’s cells and effectively cured the sepsis.
However, the most surprising observation was that resistance to this compound went virtually undetected and it showed efficacy against both gram-positive and gram-negative bacteria. The presumption was due to the fact it interferes with numerous membrane-based functions.
While the study clearly presents lessons on enhancing business, testing, and innovation models, it also underscores the importance of allowing flexibility for alternative approaches in R&D.
Advances in new therapies that are benefiting from this flexibility include RNA editing, which is nearing the stage of clinical trials. Simple innovations in therapeutic approaches can challenge decades-old susceptibility tests. However, these innovations often encounter resistance because of the prevailing attitude of “that’s the way it’s always been.”
It demonstrates that resistance goes beyond the realm of therapeutic challenges and becomes a task of overcoming the general mindset across the industry, i.e., getting people to change their routine habits and ways of thinking.
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