Editorial: Beyond Antimicrobials: Non-traditional Approaches to Combating Multidrug-Resistant Bacteria

Abstract

Editorial on the Research Topic Beyond Antimicrobials: Non-traditional Approaches to Combating Multidrug-Resistant Bacteria Since the time of Galen and Hippocrates, medicine has had a slow progression, with each new advance improving the length and quality of patients' lives. By the nineteenth century, medical science had even begun to understand the concept of vaccinations and had started to make substantial inroads into the prevention of communicable diseases. Despite this, diagnosis with a bacterial infection frequently remained tantamount to a death sentence. With treatment essentially limited to supportive care, patients were left to either recover or die. But in the twentieth century, the discovery of antimicrobials changed this. It is not an overstatement to say that medical science changed forever, because this allowed the development of countless medical advances that fall under the classification of internal medicine. Ranging from simple surgeries like the removal of an inflamed appendix to the complete replacement of whole organs and organ systems, not to mention the placement of various medical devices that have improved the lives of countless patients. Despite this, infectious diseases, including those caused by bacteria, remain the leading cause of premature death worldwide. Problematically, this trend looks as though it will worsen, as both the number and the proportion of clinically relevant bacterial strains and species exhibiting antimicrobial resistance is on the rise. For the ESKAPE pathogens (i.e., Enterococcus faecium, Staphylcoccus aureus, Klebsiella pneumonia, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp.), not only are single and multidrug resistance common, but pandrug resistance has begun to be clinically observed (Mulani et al., 2019). Overall, for the first time in nearly a century, the spread of antimicrobial resistance has begun to lead to regressions in treatment options and the re-emergence of formerly treatable infections as real threats to community health. While the public remains largely complacent to the threat, experts in healthcare warn of the “galloping hoofbeats of the horsemen of the apocalypse” and the very real possibility that voluntary medical procedures will become a historical phenomenon within the next century, even in the developed world (Projan, 2003). Further complicating matters, antimicrobial drug discovery has dramatically slowed over the last 20 years, with a paucity of new treatments on the market or in development pipelines. The most obvious problem is scientific. Using the same methods to screen the same libraries leads to the same treatments, which are now ineffective. Finding new methods and new libraries is one option, but it is laborious and requires a leap of faith that the new method will be effective. A more serious problem is economic (Ventola, 2015; Renwick and Mossialos, 2018). For large pharmaceutical companies, the return on investment for antimicrobials tends to be much lower than for lifestyle medicines, which are intended for disease maintenance rather than a cure. For antimicrobials, maintenance is often impractical or impossible. Moreover, identification, development, design, regulatory approval, and marketing are necessary steps for a large pharmaceutical corporation to get a new treatment into clinics for patients. These steps can take from 5 to 20 years. Meanwhile, antimicrobial resistance frequently arises in less than five, particularly when antimicrobial stewardship (i.e., limiting antimicrobial use to last-ditch cases, preventing agricultural or household cleaner use, etc.) is not stringently maintained (Rice, 2018). Worse yet, pricing for antibiotics tends to be lower than for other drugs that have such outsized impacts on morbidity and mortality (e.g., cancer drugs). Finally, the same stewardship programs limit antibacterial use to prolong clinical utility, also artificially curtailing the market size. Cumulatively, these effects result in a monetary loss for the company. A final obstacle is the incredible regulatory hurdles, particularly in the US, that stand in the way of companies and organizations willing to take on the burden (Metlay et al., 2006). For example, due to the transience of bacterial infections, it is often difficult to find enough patients for large-scale human trials. Another difficulty is the approval process (particularly the US FDA, the EMA has been generally more tractable) that places an undue burden of proof on pharmaceutical companies (e.g., patients only qualify as having been successfully treated if the causative bacterium is identified in complex infections like bacterial pneumonia, difficulty in demonstrating superiority of new treatments to existing therapy instead of non-inferiority to current treatments, etc.). Regulatory and legislative efforts have been initiated in the past 15 years to combat these trends, but rectification has occurred at a glacial pace (Humphries et al., 2018; Sfeir, 2018). Clearly, it behooves us to seek out alternative mechanisms of treatment to address this growing gap. Therefore, currently there is an increased interest in alternative approaches to the treatment of drug-resistant bacteria. A number of these strategies are presented in this Research Topic. To mitigate the resistance emergence, one increasingly viable option is the discovery and development of the therapeutic chemicals that target bacterial virulence, rather than bacterial growth. In most cases (with the notable exception of immune-related pathology activated by structural components), the mere presence of bacterial cells is insufficient to trigger disease. Instead, pathogenic microorganisms produce various virulence factors that are responsible for the damage inflicted on the host. There is mounting evidence that these pathogenic determinants are viable pharmaceutical targets; treatments that...