𝐂𝐥𝐢𝐧𝐢𝐜𝐚𝐥𝐥𝐲 𝐫𝐞𝐥𝐞𝐯𝐚𝐧𝐭 𝐚𝐧𝐭𝐢𝐛𝐢𝐨𝐭𝐢𝐜 𝐫𝐞𝐬𝐢𝐬𝐭𝐚𝐧𝐜𝐞 𝐠𝐞𝐧𝐞𝐬 𝐚𝐫𝐞 𝐥𝐢𝐧𝐤𝐞𝐝 𝐭𝐨 𝐚 𝐥𝐢𝐦𝐢𝐭𝐞𝐝 𝐬𝐞𝐭 𝐨𝐟 𝐭𝐚𝐱𝐚 𝐰𝐢𝐭𝐡𝐢𝐧 𝐠𝐮𝐭 𝐦𝐢𝐜𝐫𝐨𝐛𝐢𝐨𝐦𝐞 𝐰𝐨𝐫𝐥𝐝𝐰𝐢𝐝𝐞

📍 Antimicrobial resistance (AR) poses a significant threat to public health, and the gut microbiota is considered a global reservoir for AR genes. This study, leveraging a comprehensive analysis of 14,850 human metagenomes, 1666 environmental metagenomes, and nearly 600,000 isolate genomes, explores the taxonomic associations, prevalence, and transfer potential of clinically relevant AR genes.

Notably, the focus is on beta-lactamase genes, specifically cephalosporinases and carbapenemases, with a particular emphasis on their taxonomic range and potential spread within diverse gut microbiota.

📍 Methods:

Dataset Collection: 14,850 human metagenomes, 1666 environmental metagenomes, and nearly 600,000 isolate genomes were analyzed to capture the diversity of AR genes.

Gene Targets: The study focused on clinically significant AR genes, including cephalosporinases (e.g., CTX-M) and carbapenemases (e.g., KPC, IMP, NDM, VIM).

Taxonomic Analysis: Utilizing bioinformatics tools, taxonomic associations of AR genes were determined at the phylum, genus, and species levels.

Single-Cell Fusion PCR: Gut microbiome samples from specific regions (India, Honduras, Pakistan, Vietnam) were analyzed using a high-sensitivity single-cell fusion PCR approach to confirm taxonomic associations of AR genes.

Key Findings:

📌 Global Prevalence and Taxonomic Distribution of Clinically Relevant AR Genes: The AR gene families conferred resistance to 18 antibiotic classes and exhibited a relatively even geographic distribution but showed differences between Western and non-Western gut microbiomes.

📌 Bimodal Distribution and Host Ranges of AR Genes:

AR gene families exhibited a bimodal distribution, being either widely distributed or restricted to specific countries.

Certain taxa, including 𝘎𝘢𝘮𝘮𝘢𝘱𝘳𝘰𝘵𝘦𝘰𝘣𝘢𝘤𝘵𝘦𝘳𝘪𝘢, 𝘉𝘦𝘵𝘢𝘱𝘳𝘰𝘵𝘦𝘰𝘣𝘢𝘤𝘵𝘦𝘳𝘪𝘢, 𝘢𝘯𝘥 𝘉𝘢𝘤𝘪𝘭𝘭𝘪, harbored a higher number of AR genes, with 𝘈𝘤𝘵𝘪𝘯𝘰𝘮𝘺𝘤𝘦𝘵𝘪𝘢, 𝘪𝘯𝘤𝘭𝘶𝘥𝘪𝘯𝘨 𝘚𝘵𝘳𝘦𝘱𝘵𝘰𝘮𝘺𝘤𝘦𝘴, also showing enrichment.

📌 Unexpected Taxonomic Restrictions of AR Gene Families:

Contrary to expectations, a subset of AR gene families, including NDM and CMY, was restricted to a single taxonomic class, challenging the assumption that AR genes associated with plasmids have broad taxonomic ranges.

Cephalosporinase genes (cepA and cblA) and the carbapenemase gene cfiA were confined to the genus Bacteroides.

📌 Factors Influencing AR Gene Prevalence:

Antibiotic use did not always correlate with AR gene prevalence in gut microbiomes. Beta-lactams, the most consumed antibiotics globally, did not lead to a proportional increase in beta-lactamase gene prevalence.

Limited presence of carbapenemases in gut microbiomes, despite the significant global consumption of carbapenems, raised questions about factors influencing AR gene prevalence.

📌 Comparative Analysis with Suspected Reservoirs:

Hospital effluent exhibited enrichment for clinically relevant AR genes, suggesting aerobic conditions favoring 𝘗𝘳𝘰𝘵𝘦𝘰𝘣𝘢𝘤𝘵𝘦𝘳𝘪𝘢 as potential carriers of diverse AR genes.

📌 Lack of Hidden Taxonomic Reservoir in Gut Microbiomes:

Using OIL-PCR, a single-cell fusion PCR approach, confirmed that known isolates sufficiently explained the taxonomic associations of clinically relevant AR gene families in gut microbiomes.

Exceptions included mcr genes, suggesting a potential undefined reservoir or low-abundance known hosts.

📌 Functional Transfer of Bacteroides-Specific Beta-Lactamases to 𝘌𝘯𝘵𝘦𝘳𝘰𝘣𝘢𝘤𝘵𝘦𝘳𝘪𝘢𝘤𝘦𝘢𝘦 :

Bacteroides-specific beta-lactamases, including cfiA and cblA, were shown to be functional in 𝘌. 𝘤𝘰𝘭𝘪 when expressed under synthetic 𝘌. 𝘤𝘰𝘭𝘪 promoters.

These beta-lactamases conferred resistance to clinically relevant antibiotics without significant growth defects in 𝘌. 𝘤𝘰𝘭𝘪.

📌 Potential Barriers to HGT Beyond 𝘉𝘢𝘤𝘵𝘦𝘳𝘰𝘪𝘥𝘦𝘴:

Despite the functional transfer of beta-lactamases, the taxonomic distribution of these genes remains restricted to 𝘉𝘢𝘤𝘵𝘦𝘳𝘰𝘪𝘥𝘦𝘴 in gut microbiomes.

The study identified potential barriers to horizontal gene transfer (HGT) beyond 𝘉𝘢𝘤𝘵𝘦𝘳𝘰𝘪𝘥𝘦𝘴, raising questions about the factors limiting the spread of clinically relevant AR genes.

📍 The study advocates for targeted strategies, such as fecal microbiota transplantation, phage therapy, and gene editing, to address specific AR gene families and mitigate the emergence of novel AR strains. Further research is needed to explore the factors influencing the taxonomic spread and persistence of AR genes over time.

Link to the article : https://tinyurl.com/56b5sbwb