No abstract

25The human gut microbiome harbors hundreds of bacterial species with 26 diverse biochemical capabilities, making it one of nature's highest density, 27 highest diversity bioreactors. Several drugs have been previously shown to be 28 directly metabolized by the gut microbiome, but the extent of this phenomenon 29 has not been systematically explored. Here, we develop a systematic screen for 30 mapping the ability of the complex human gut microbiome to biochemically 31 transform small molecules (MDM-Screen), and apply it to a library of 575 clinically 32 used oral drugs. We show that 13% of the analyzed drugs, spanning 28 33 pharmacological classes, are metabolized by a single microbiome sample. In a 34 proof-of-principle example, we show that microbiome-derived metabolism occurs 35 in vivo, identify the genes responsible for it, and provide a possible link between 36 its consequences and clinically observed features of drug bioavailability and 37 toxicity. Our findings reveal a previously underappreciated role for the gut 38 microbiome in drug metabolism, and provide a comprehensive framework for 39 characterizing this important class of drug-microbiome interactions. 40 41 42 43 44 45 46 47iii) a defined mouse colonization assay for assessing the effect of the microbiome on the 94 pharmacokinetics of selected drugs. Using MDM-Screen with 575 clinically used, orally 95 administered, small molecule drugs, we discovered that 13% of them can be subject to 96 MDM. As a proof-of-principle example, we selected one of these transformations -97 MDM deglycosylation of fluoropyrimidines -for further functional investigations. We 98 identify microbiome-derived species and enzymes responsible for this transformation, 99show that it occurs in vivo in a microbiome-dependent manner, and provide evidence 100 that its consequences may explain outcomes already observed in the clinic. Our screen 101 described here, and the findings obtained from it represent the first systematic map of 102 microbiome-derived metabolism of clinically used drugs, and provide a framework for 103incorporating an "MDM" module in future drug development pipelines.

The prevalence and cost of wounds pose a challenge to patients as well as the healthcare system. Wounds can involve multiple tissue types and, in some cases, become chronic and difficult to treat. Comorbidities may also decrease the rate of tissue regeneration and complicate healing. Currently, treatment relies on optimizing healing factors rather than administering effective targeted therapies. Owing to their enormous diversity in structure and function, peptides are among the most prevalent and biologically important class of compounds and have been investigated for their wound healing bioactivities. A class of these peptides, called cyclic peptides, confer stability and improved pharmacokinetics, and are an ideal source of wound healing therapeutics. This review provides an overview of cyclic peptides that have been shown to promote wound healing in various tissues and in model organisms. In addition, we describe cytoprotective cyclic peptides that mitigate ischemic reperfusion injuries. Advantages and challenges in harnessing the healing potential for cyclic peptides from a clinical perspective are also discussed. Cyclic peptides are a potentially attractive category of wound healing compounds and more research in this field could not only rely on design as mimetics but also encompass de novo approaches as well.