Review 1: "The Riboflavin Biosynthetic Pathway as a Novel Target for Antifungal Drugs Against Candida Species"

RR\ID Evidence Scale rating by reviewer:

• Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: The work presents a valuable functional analysis of the riboflavin biosynthetic pathway in C. albicans and C. glabrata, two of the most important fungal human pathogens. The identification of the riboflavin transporter in C. albicans is also an important contribution of the work, especially because it required considerable efforts as the most promising candidate genes based in sequence similarity were actually not involved in riboflavin intake. 

Even when I do not find majors issues that cannot be corrected through a full peer-review process, I think that the main claim that the riboflavin pathway is a novel target for antifungal drugs is not fully supported by the presented data. Two aspects are missing to that respect. First, it would be necessary to show that the pathway is essential for virulence of these species in animal models of infection, preferentially commensal and systemic models. Although the authors have performed this type of assays in the past for one of these genes in C. albicans, they barely incorporate those results in this work. It is contrasting that in their previous study with animal assays they were more cautions in their conclusions. Second, it has not been shown that these enzymes can be actually inhibited employing drugs. This aspect is not included in their discussion where at least previous evidence that this pathway is druggable would be very informative. Overall, I think the work is valuable, but the main claim should be toned-down.