International travel contributes to the global spread of antimicrobial resistance. Travelers’ diarrhea exacerbates the risk of acquiring multidrug-resistant organisms and can lead to persistent gastrointestinal disturbance post-travel. However, little is known about the impact of diarrhea on travelers’ gut microbiomes, and the dynamics of these changes throughout travel. Here, we assembled a cohort of 159 international students visiting the Andean city of Cusco, Peru and applied next-generation sequencing techniques to 718 longitudinally-collected stool samples. We find that gut microbiome composition changed significantly throughout travel, but taxonomic diversity remained stable. However, diarrhea disrupted this stability and resulted in an increased abundance of antimicrobial resistance genes that can remain high for weeks. We also identified taxa differentially abundant between diarrheal and non-diarrheal samples, which were used to develop a classification model that distinguishes between these disease states. Additionally, we sequenced the genomes of 212 diarrheagenic Escherichia coli isolates and found those from travelers who experienced diarrhea encoded more antimicrobial resistance genes than those who did not. In this work, we find the gut microbiomes of international travelers’ are resilient to dysbiosis; however, they are also susceptible to colonization by multidrug-resistant bacteria, a risk that is more pronounced in travelers with diarrhea.
Inactivation of tetracycline antibiotics by tetracycline destructases (TDases) remains a clinical and agricultural threat. TDases can be classified as type 1 Tet(X)-like TDases and type 2 soil-derived TDases. Type 1 TDases are widely identified in clinical pathogens. A combination therapy of tetracycline and a TDase inhibitor is much needed to rescue the clinical efficacy of tetracyclines. Anhydrotetracycline is a pan-TDase inhibitor that inhibits both type 1 and type 2 TDases. Here, we present structural, biochemical, and phenotypic evidence that anhydrotetracycline binds in a substrate-like orientation and competitively inhibits the type 1 TDase Tet(X6) to rescue tetracycline antibiotic activity as a sacrificial substrate. Anhydrotetracycline interacting residues of Tet(X6) are conserved within type 1 TDases, indicating a conserved binding mode and mechanism of inhibition. This mode of binding and inhibition is distinct from anhydrotetracycline’s inhibition of type 2 TDases. This study forms the framework for development of next-generation therapies to counteract enzymatic tetracycline resistance.
There is a paucity of research on detailed antibiotic resistome and microbiome diversity of Indian hospital wastewater. This study reports the predominance of clinically concerning ARGs such as the beta-lactamases
bla
NDM
and
bla
OXA
and the colistin resistance gene
mcr
and their association with the microbiome in six different Indian hospital wastewaters of both urban and rural origin.
Tetracyclines (TCs) are an important class of antibiotics
threatened
by an emerging new resistance mechanismenzymatic inactivation.
These TC-inactivating enzymes, also known as tetracycline destructases
(TDases), inactivate all known TC antibiotics, including drugs of
last resort. Combination therapies consisting of a TDase inhibitor
and a TC antibiotic represent an attractive strategy for overcoming
this type of antibiotic resistance. Here, we report the structure-based
design, synthesis, and evaluation of bifunctional TDase inhibitors
derived from anhydrotetracycline (aTC). By appending a nicotinamide
isostere to the C9 position of the aTC D-ring, we generated bisubstrate
TDase inhibitors. The bisubstrate inhibitors have extended interactions
with TDases by spanning both the TC and presumed NADPH binding pockets.
This simultaneously blocks TC binding and the reduction of FAD by
NADPH while “locking” TDases in an unproductive FAD
“out” conformation.
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