{"id":541645,"date":"2026-07-24T08:26:12","date_gmt":"2026-07-24T08:26:12","guid":{"rendered":"https:\/\/www.newsbeep.com\/nz\/541645\/"},"modified":"2026-07-24T08:26:12","modified_gmt":"2026-07-24T08:26:12","slug":"mechanistic-and-evolutionary-determinants-of-cefiderocol-resistance-in-kpc-producing-pseudomonas-aeruginosa","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/nz\/541645\/","title":{"rendered":"Mechanistic and evolutionary determinants of cefiderocol resistance in KPC-producing Pseudomonas aeruginosa"},"content":{"rendered":"<p>Cefiderocol (FDC), a siderophore cephalosporin, shows potent activity against difficult-to-treat Pseudomonas aeruginosa. We analyzed 25 clinical KPC-variant-producing P. aeruginosa from China (2016-2025) and laboratory-induced FDC-resistant strains (KPC-2\/ST463, a high-risk P. aeruginosa clone in China), using WGS, RNA-seq, RT-qPCR, metabolomics, and QM\/MM simulations. Clinical isolates were dominated by KPC-33\/ST463, highly resistant to ceftazidime-avibactam (25\/25) but largely FDC-susceptible (22\/25). FDC-induced strains acquired blaKPC-33 mutations and siderophore receptor disruptions. QM\/MM metadynamics revealed that KPC-33 optimized Ser70 catalytic-site dynamics, reducing the hydrolysis free energy barrier (\u0394G\u2021 from 15.2 to 13.0\u2009kcal\/mol) and increasing catalytic efficiency (kcat\/KM from 50 to 2000 M\u207b\u00b9s\u207b\u00b9). The difference in binding pockets between receptor and ligand required the Ser70 hydroxyl oxygen atom of KPC-2 to travel longer distances to complete nucleophilic attack and acylation. We observed a bifurcated response to antibiotic pressure: clinical adaptation involved multi-scale regulatory shifts in iron uptake and efflux, whereas laboratory induction triggered acute genetic transitions in primary resistance determinants. Global epidemiology shows widespread KPC-plasmid dissemination, particularly in Asia. Monitoring plasmid backbones, \u03a9-loop KPC variants, and siderophore receptor status may guide FDC therapy and anticipate resistance in high-risk strains.<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/www.newsbeep.com\/nz\/wp-content\/uploads\/2026\/07\/42003_2026_10726_Figa_HTML.png\" alt=\"\" loading=\"lazy\" width=\"685\" height=\"909\"\/><\/p>\n","protected":false},"excerpt":{"rendered":"Cefiderocol (FDC), a siderophore cephalosporin, shows potent activity against difficult-to-treat Pseudomonas aeruginosa. We analyzed 25 clinical KPC-variant-producing P.&hellip;\n","protected":false},"author":2,"featured_media":541646,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[12591,2294,6422,6475,111,139,69,147],"class_list":["post-541645","post","type-post","status-publish","format-standard","has-post-thumbnail","category-science","tag-antimicrobial-resistance","tag-general","tag-life-sciences","tag-molecular-medicine","tag-new-zealand","tag-newzealand","tag-nz","tag-science"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/541645","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/comments?post=541645"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/541645\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media\/541646"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media?parent=541645"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/categories?post=541645"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/tags?post=541645"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}