Beyond Antimicrobials: Non-Traditional Approaches to Combating Multidrug-Resistant Bacteria

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Background

Antibiotic resistance is an ever-growing public health concern, exacerbated by the recent appearance of bacteria resistant to all available antibiotics. Bacterial infections remain a leading cause of death worldwide. 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, even in the developed world. Further complicating matters, antimicrobial drug discovery has dramatically slowed over the last twenty years, with a paucity of new treatments on the market or in development pipelines. A variety of biological, financial, and regulatory hurdles indicate that this situation is likely to get much worse before it improves. Clearly, it behooves us to seek out alternative mechanisms of treatment to address this growing gap.

One increasingly viable option is the development of therapies that target pathogen 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 compromising one or more of these factors (i.e., anti-virulence) can often largely, or even completely, mitigate disease. Anti-virulence drugs should reduce antibiotic use and, ultimately, decrease the development of antibiotic resistance, as they should not impose strong selective pressure on bacteria that favors the evolution of mechanisms of resistance and persistence. Additionally, because they do not affect bacterial cell viability, they should not disrupt beneficial microbiota. Anti-virulence compounds could serve as alternatives or adjuncts to traditional antibiotics and to potentiate their efficacy, generating even more effective treatment options in particular against multi-drug resistant pathogens.

Several other alternatives to antibiotics also show considerable promise in fighting bacterial infections. Recent advances in our understanding of the role of the host microbiota in protecting against various infections have pushed forward the field of fecal microbiota transplantation; clinical studies increasingly suggest that this type of therapy may have significant importance in the near future. The clinical value of narrow specificity antibacterial agents, such as bacteriophages, is increasingly recognized as they can specifically eliminate an infectious bacterial strain or species without affecting the host microbiota. These viruses can be used as highly evolved antibacterial agents, able to effectively amplify at the site of infection and to cause the death and lysis of their bacterial targets. They show substantial promise when used whole, but purified enzymes from these viruses (ie. lysins) have also been effective. Other approaches such as antimicrobial peptides or phytochemicals may also prove to have significant utility against multidrug resistant infections.

The aim of this Research Topic is to publish Original Research papers, Reviews, or Mini-Reviews focusing on the discovery or development of new drugs, or the repurposing of known therapeutics, for targeting virulence determinants as means to mitigate bacterial disease.

Keywords: Drug discovery, Infectious Disease, Anti-Virulence, Anti-Infectives, Host-Microbe Interactions

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