Insights into the Vibrio Genus: A One Health Perspective from Host Adaptability and Antibiotic Resistance to In Silico Identification of Drug Targets

Abstract

The genus Vibrio comprises an important group of ubiquitous bacteria of marine systems with a high infectious capacity for humans and fish, which can lead to death or cause economic losses in aquaculture. However, little is known about the evolutionary process that led to the adaptation and colonization of humans and also about the consequences of the uncontrollable use of antibiotics in aquaculture. Here, comparative genomics analysis and functional gene annotation showed that the species more related to humans presented a significantly higher amount of proteins associated with colonization processes, such as transcriptional factors, signal transduction mechanisms, and iron uptake. In comparison, those aquaculture-associated species possess a much higher amount of resistance-associated genes, as with those of the tetracycline class. Finally, through subtractive genomics, we propose seven new drug targets such as: UMP Kinase, required to catalyze the phosphorylation of UMP into UDP, essential for the survival of bacteria of this genus; and, new natural molecules, which have demonstrated high affinity for the active sites of these targets. These data also suggest that the species most adaptable to fish and humans have a distinct natural evolution and probably undergo changes due to anthropogenic action in aquaculture or indiscriminate/irregular use of antibiotics.

Keywords: Vibrio; antibiotic resistance; genomic islands; molecular docking; one health; pan-resistome; subtractive genomics; virulence factors.

Figure 1

COG classifications made by eggNOG-mapper. Each category is represented by a letter, and each column corresponds to a group of pathogens. The HP group is red, green RHP, and blue FP.

Figure 2

Genomic islands present in the genome of Vibrio parahaemolyticus. The BRIG analysis for the two Vibrio spp. chromosomes (Ch1-A; Ch2-B). In the order: Vibrio parahaemolyticus, strains RIMD, Vb0624, and 2012AW224, Vibrio cholerae strain 2012El 2176, Vibrio natriegens, strain COUG 16373. On the outer ring are plotted the genomic islands. In red are the pathogenicity islands, in green are the resistance islands, and in yellow are the metabolic islands predicted by GIPSy. In blue, there are small, enumerated traces, which correspond to the position of the iron metabolism proteins. C-Highlighted is the region of the proteins present in PAI2, in order: WP_005491112.1, WP_005491087.1, WP_021451074.1 and WP_005457554.1.

Figure 3

Clustering resistance genes from the PRAP tool using the CARD database. On the right are the genomes of each species used, below are the antibiotic classes, and on the left and above are the cluster formation process based on antibiotic resistance. From 0 to 4 indicates the number of genes associated with the antibiotic classes.

Figure 4

An overview of the pan-resistome of the Vibrio genus. Each bar per column corresponds to an ARG of a given genome. Each color represents resistance to a class of antibiotics, such as pink to tetracycline and light green to cephalosporin. For more details, check the chart in Supplementary Material 2.

Figure 5

An overview of the pan-resistome of Vibrio cholerae. A total of 92 complete genomes were used for ARG prediction.

Figure 6

Development of the pan-resistome of Vibrio cholerae. Used the power law and combinatorial analysis to predict the addition of new ARGs per genome in the species. The purple line comprises the fitted curve of the pan-resistome appropriate for its development, while the bars in blue represent the addition of new ARGs. The same for the core-resistome in orange.

Figure 7

Docking results for HP and FP. (A–C) (Red) correspond to the results of HP docking, and (D–G) (Blue) correspond to the result of the second docking of the FP group. These results contain the respective drug targets with the best interactions with ZINC compounds. On the left are ribbons on the one, and on the right, the protein has its surface.

Figure 8

Graphical conclusion. Genomes of fish and human pathogens were used for core genome identification, and comparative analyses demonstrated the ability of pathogens to adapt to the human host linked to horizontal gene transfer and iron uptake, and the impact of selective pressure of aquaculture on the dissemination of resistance genes. Finally, a pipeline of subtractive genomics and molecular docking was performed to identify potential natural compounds capable of inhibiting the active site of the identified drug targets.