A New Approach to Treating “Superbugs”
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Antibiotic resistance poses a significant threat to modern medicine and global public health, with the spread of multi-drug resistant “superbugs” leaving limited treatment options for an increasing number of infections. According to the World Health Organization, the pipeline of new antibiotics is running dry, and only a small portion of antibiotics in development are likely to be effective against the most dangerous antibiotic-resistant bacteria. A further issue is that the continued overuse and misuse of antibiotics will likely lead to even more bacteria adapting and evolving resistance. Alternative antibacterials are urgently needed, especially for priority pathogens such as carbapenem-resistant Enterobacteriaceae (CRE).
In a study recently published in Scientific Reports, a team of scientists led by Justin Schaal, PhD, assistant professor of research pathology, Keck School of Medicine of USC, demonstrate the potential of a new bioengineered peptide molecule – MTD12813 – to be used as a host-directed antibacterial. Inspired by theta-defensins, a type of antimicrobial peptide found in Old World monkeys (OWM), MTD12813 was shown to be highly effective at treating Klebsiella pneumoniae in a mouse model.
Technology Networks had the pleasure of speaking to Justin to learn more about MTD12813, its mode of action and how it addresses some of the shortcomings of traditional antibiotics.
Anna MacDonald (AM): Can you tell us more about theta-defensins and why they are of interest?
Justin Schaal (JS): Theta-defensins are the only known backbone cyclic peptides found in the animal kingdom, meaning they are a complete circle of amino acids with no free ends. This fact alone makes them intriguing molecules, however their activities in the natural host and their potential therapeutic applications make them fascinating. Since their discovery by senior author Michael Selsted more than 20 years ago, we have demonstrated theta-defensins possess both antimicrobial activities and immunomodulatory properties. One of the more interesting observations has been how the natural hosts of theta-defensins, OWM, respond to infections. Multiple studies have shown that OWM such as rhesus monkeys and baboons are many times more resistant to bacterial infections than humans despite having similar immune systems to our own. We began to ask why. Despite our similar immune systems, humans (and other hominins) were found to have a stop codon in our genes preventing the production of theta-defensins by our white blood cells. As a result, during primate evolution, the ability to make these unique molecules was lost. Is that why we are more susceptible to infections? If so, could we in a “retroevolutionary” way reintroduce theta-defensins therapeutically? Exploring the potential therapeutic utility of theta-defensins has become the focus of our research group, not only in infection, but in diseases of autoimmunity, chronic inflammation and cancer. As an example of their therapeutic potential, ORTD-1, the prototype theta-defensin just completed a Phase IB human trial for use in treating rheumatoid arthritis.
AM: How was MTD12813 in particular identified for further preclinical evaluation?
JS: Utilizing the unique structure of theta-defensins as a molecular scaffold we designed a library of bioinspired analogs to explore the effect of various modifications to the naturally produced peptides. We analyzed numerous properties of these analogs to identify a lead series from which MTD12813 emerged as the most promising in terms of stability, efficacy and safety in treating multi-drug resistant bacteria. Importantly, therapeutic efficacy correlated with moderation of otherwise dysregulated inflammation which often leads to shock and death.
AM: What did your findings show about the effects of MTD12813 in CRE sepsis? How does it promote bacterial clearance?
JS: Our findings demonstrated MTD12813 treatment elicits three critical responses from the infected host. First, MTD12813 treatment promotes the rapid systemic clearance of the infection by stimulating host immune cells to recognize, attack and destroy the bacteria. Secondly, the peptide promoted the recruitment of neutrophils, cells that ingest and kill bacteria. Third, as mentioned above, MTD12813 modulated proinflammatory responses associated with septic shock.
AM: How does the mode of action of MTD12813 compare to traditional antibiotics? What are the advantages of this approach?
JS: Antibiotics are designed to kill bacteria or inhibit their replication. MTD12813 does not kill bacteria but rather stimulates the clearance of the pathogen by recruiting neutrophils and promoting the host’s intrinsic ability to kill and clear microbial invaders. Antibiotics directly interact with bacteria which are capable of rapid adaptation and evolution, resulting in drug resistance. Since MTD12813 works through the host, the opportunity for bacteria to evolve resistance is greatly limited. Indeed, the bacteria we used in these studies were already resistant to nearly all antibiotics. Single dose administration of MTD12813 was highly effective in promoting bacterial clearance and treating otherwise fatal infection.
AM: MTD12813 was also shown to modulate pathogenic cytokine responses. What is the significance of this?
JS: Uncontrolled bacterial infections often result in the development of sepsis, a disease state of dysregulated host immune responses driven by a “cytokine storm” that causes significant collateral damage to host tissues and is associated with high mortality rates. We showed MTD12813 significantly modulated cytokine responses and rapidly restored them to near homeostatic levels, without causing immunosuppression. This immunomodulatory activity protects the infected host from the deleterious effects of an overreacting immune response. The ability to control pathogenic inflammation while concomitantly promoting pathogen clearance makes MTD12813 a promising candidate to treat bacterial sepsis, a disorder for which there are few effective therapies.
AM: Were any side effects observed in the study? How did they compare to effects caused by traditional antibiotics?
JS: There were no observable side effects. In acute toxicity studies the maximum tolerated dose was more than 50 times the effective dose. Compared to true “drugs of last resort” used to treat CRE infections, such as colistin which has well known toxicities near its effective dose levels, MTD12813 has a much greater safety window.
AM: Compared to traditional antibiotics, how easy are minimized theta-defensins (MTD) to produce, transport and store?
JS: While MTDs are larger and structurally more complex molecules compared to most traditional antibiotics, they are readily produced by standard chemical synthesis protocols. Because of their novel cyclic structures, they are exceedingly stable and may be transported as a dry powder or in solution.
AM: In terms of next steps, what further research do you have planned?
JS: Ongoing studies include standard IND-enabling preclinical safety studies, assessment of MTD12813 efficacy against an expanded panel of bacterial pathogens, and further characterization of the pathways that underly the augmentation of the host’s ability to fend off infections caused by multi-drug resistant pathogens including the “superbugs” used in our study.
Justin Schaal was speaking to Anna MacDonald, Science Writer for Technology Networks.