{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:59:19Z","timestamp":1793066359192,"version":"4.5.0"},"reference-count":26,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T00:00:00Z","timestamp":1598313600000},"content-version":"vor","delay-in-days":15,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccby_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1U19AI142731"],"award-info":[{"award-number":["1U19AI142731"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10-OD023524"],"award-info":[{"award-number":["S10-OD023524"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1117928"],"award-info":[{"award-number":["OPP1117928"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Semisynthetic rifamycin derivatives such as rifampicin (Rif) are first line treatments for tuberculosis and other bacterial infections. Historically, synthetic modifications made to the C-3\/C-4 region of the rifamycin naphthalene core, like those seen in Rif, have yielded the biggest improvements in pharmacological properties. However, modifications found in natural product rifamycin congeners occur at other positions in the structure. The kanglemycins (Kangs) are a family of rifamycin congeners with a unique collection of natural modifications including a dimethylsuccinic acid appended to their polyketide backbone. These modifications confer activity against the single most common clinically relevant Rif resistance (RifR) mutation in the antibiotic\u2019s target, the bacterial RNA polymerase (RNAP). Here we evaluate the in vivo efficacy of Kang A, the parent compound in the Kang family, in a murine model of bacterial peritonitis\/sepsis. We then set out to improve its potency by combining its natural tailoring modifications with semisynthetic derivatizations at either its acid moiety or in the C-3\/C-4 region. A collection of C-3\/C-4 benzoxazino Kang derivatives exhibit improved activity against wild-type bacteria, and acquire activity against the second most common clinically relevant RifR mutation. The semisynthetic analogue 3\u2032-hydroxy-5\u2032-[4-isobutyl-1-piperazinyl] benzoxazino Kang A (Kang KZ) protected mice against infection with either Rif sensitive MRSA or a highly virulent RifRStaphylococcus \u00a0aureus strain in a neutropenic peritonitis\/sepsis model and led to reduced bacterial burdens. The compounds generated in this study may represent promising candidates for treating RifR infections.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00223","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T17:20:08Z","timestamp":1597080008000},"page":"2431-2440","source":"Crossref","is-referenced-by-count":20,"title":["A Semisynthetic Kanglemycin Shows In Vivo Efficacy against High-Burden Rifampicin\nResistant Pathogens"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-3430","authenticated-orcid":true,"given":"James","family":"Peek","sequence":"first","affiliation":[{"name":"The Rockefeller University , , 1230 York Avenue , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Xu","sequence":"additional","affiliation":[{"name":"Belfer Research Building , , 413 E 69th Street , , ,","place":["New York, New York, United States, 10021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health , , 340 Kingsland Street , , ,","place":["Nutley, New Jersey, United States, 07110"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shraddha","family":"Suryavanshi","sequence":"additional","affiliation":[{"name":"Rutgers, The State University of New Jersey , , 225 Warren Street , , ,","place":["Newark, New Jersey, United States, 07103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health , , 340 Kingsland Street , , ,","place":["Nutley, New Jersey, United States, 07110"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Russo","sequence":"additional","affiliation":[{"name":"Rutgers, The State University of New Jersey , , 225 Warren Street , , ,","place":["Newark, New Jersey, United States, 07103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Park","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health , , 111 Ideation Way , , ,","place":["Nutley, New Jersey, United States, 07110"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Perlin","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health , , 111 Ideation Way , , ,","place":["Nutley, New Jersey, United States, 07110"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean F.","family":"Brady","sequence":"additional","affiliation":[{"name":"The Rockefeller University , , 1230 York Avenue , , ,","place":["New York, New York, United States, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,8,10]]},"reference":[{"key":"2026090216342115800_cit1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.tube.2010.02.001","article-title":"Rifamycins--obstacles and opportunities","volume":"90","author":"Aristoff","year":"2010","journal-title":"Tuberculosis (Oxford, U. K.)"},{"issue":"Suppl\n3","key":"2026090216342115800_cit2","doi-asserted-by":"publisher","first-page":"S402","DOI":"10.1093\/clinids\/5.Supplement_3.S402","article-title":"History of the development of rifampin","volume":"5","author":"Sensi","year":"1983","journal-title":"Clin.\nInfect. Dis."},{"key":"2026090216342115800_cit3","doi-asserted-by":"publisher","first-page":"e10","DOI":"10.1016\/S2214-109X(14)70361-4","article-title":"The WHO 2014 global\ntuberculosis report--further to go","volume":"3","author":"Zumla","year":"2015","journal-title":"Lancet Glob\nHealth"},{"key":"2026090216342115800_cit4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1054\/tuld.1998.0002","article-title":"Molecular genetic basis of antimicrobial agent resistance\nin Mycobacterium tuberculosis: 1998 update","volume":"79","author":"Ramaswamy","year":"1998","journal-title":"Tuber Lung Dis"},{"key":"2026090216342115800_cit5","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.7164\/antibiotics.34.1026","article-title":"Antibacterial activity of DL 473, a new semisynthetic\nrifamycin derivative","volume":"34","author":"Arioli","year":"1981","journal-title":"J. Antibiot."},{"key":"2026090216342115800_cit6","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1021\/jm00143a010","article-title":"Synthesis and antibacterial activity of some esters,\namides, and hydrazides of 3-carboxyrifamycin S. Relationship between\nstructure and activity of ansamycins","volume":"24","author":"Bellomo","year":"1981","journal-title":"J. Med.\nChem."},{"key":"2026090216342115800_cit7","doi-asserted-by":"publisher","first-page":"114758","DOI":"10.1039\/C6RA22880A","article-title":"Semi-synthetic\nzwitterionic rifamycins: a promising class of antibiotics; survey\nof their chemistry and biological activities","volume":"6","author":"Bujnowski","year":"2016","journal-title":"RSC Adv."},{"key":"2026090216342115800_cit8","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.7164\/antibiotics.34.1033","article-title":"New rifamycins modified at positions 3 and 4. Synthesis,\nstructure and biological evaluation","volume":"34","author":"Marsili","year":"1981","journal-title":"J. Antibiot."},{"key":"2026090216342115800_cit9","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.7164\/antibiotics.33.1193","article-title":"Biological activity of a new class\nof rifamycins. Spiro-piperidyl-rifamycins","volume":"33","author":"Sanfilippo","year":"1980","journal-title":"J.\nAntibiot."},{"key":"2026090216342115800_cit10","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1021\/jm00335a005","article-title":"Rifamycins XXXV. Amides and Hydrazides\nof Rifamycin B.","volume":"7","author":"Sensi","year":"1964","journal-title":"J. Med. Chem."},{"key":"2026090216342115800_cit11","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1248\/cpb.41.148","article-title":"Synthesis\nand biological activity of 3\u2032-hydroxy-5\u2032-aminobenzoxazinorifamycin\nderivatives","volume":"41","author":"Yamane","year":"1993","journal-title":"Chem. Pharm. Bull."},{"key":"2026090216342115800_cit12","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/S0092-8674(01)00286-0","article-title":"Structural\nmechanism for rifampicin inhibiton of bacterial RNA polymerase","volume":"104","author":"Campbell","year":"2001","journal-title":"Cell"},{"key":"2026090216342115800_cit13","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.cell.2005.07.014","article-title":"Allosteric modulation of the RNA\npolymerase catalytic reaction is an essential component of transcription\ncontrol by rifamycins","volume":"122","author":"Artsimovitch","year":"2005","journal-title":"Cell"},{"key":"2026090216342115800_cit14","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.1016\/j.bmcl.2007.08.048","article-title":"Preparation and in vitro anti-staphylococcal\nactivity of novel 11-deoxy-11-hydroxyiminorifamycins","volume":"17","author":"Li","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090216342115800_cit15","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.7164\/antibiotics.40.1733","article-title":"CGP 4832,\na new semisynthetic rifamycin derivative highly active against some\ngram-negative bacteria","volume":"40","author":"Wehrli","year":"1987","journal-title":"J. Antibiot."},{"key":"2026090216342115800_cit16","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.molcel.2018.08.028","article-title":"Mode of action\nof kanglemycin A, an ansamycin natural product that is active against\nrifampicin-resistant Mycobacterium tuberculosis","volume":"72","author":"Mosaei","year":"2018","journal-title":"Mol. Cell"},{"key":"2026090216342115800_cit17","doi-asserted-by":"publisher","first-page":"4147","DOI":"10.1038\/s41467-018-06587-2","article-title":"Rifamycin\ncongeners kanglemycins are active against rifampicin-resistant bacteria\nvia a distinct mechanism","volume":"9","author":"Peek","year":"2018","journal-title":"Nat. Commun."},{"key":"2026090216342115800_cit18","doi-asserted-by":"publisher","first-page":"264","DOI":"10.7164\/antibiotics.41.264","article-title":"Isolation and structure\nof a new ansamycin antibiotic kanglemycin A from a Norcardia","volume":"41","author":"Wang","year":"1988","journal-title":"J. Antibiot."},{"key":"2026090216342115800_cit19","doi-asserted-by":"publisher","first-page":"6250","DOI":"10.1128\/AAC.01060-12","article-title":"Frequency,\nspectrum, and nonzero fitness costs of resistance to myxopyronin in Staphylococcus aureus","volume":"56","author":"Srivastava","year":"2012","journal-title":"Antimicrob.\nAgents Chemother."},{"key":"2026090216342115800_cit20","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1128\/AAC.35.3.542","article-title":"In vitro antimycobacterial\nactivities of newly synthesized benzoxazinorifamycins","volume":"35","author":"Saito","year":"1991","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090216342115800_cit21","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.1128\/AAC.40.11.2655","article-title":"Comparative\nantimycobacterial activities of rifampin, rifapentine, and KRM-1648\nagainst a collection of rifampin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations","volume":"40","author":"Moghazeh","year":"1996","journal-title":"Antimicrob.\nAgents Chemother."},{"issue":"9","key":"2026090216342115800_cit22","doi-asserted-by":"publisher","first-page":"3974","DOI":"10.1128\/AAC.49.9.3974-3976.2005","article-title":"Activities of rifamycin derivatives against wild-type\nand rpoB mutants of Chlamydia trachomatis","volume":"49","author":"Xia","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090216342115800_cit23","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1128\/AAC.50.3.827-834.2006","article-title":"In vitro activity of novel rifamycins\nagainst rifamycin-resistant Staphylococcus aureus","volume":"50","author":"Murphy","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090216342115800_cit24","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/ja.2008.65","article-title":"Rifalazil retains activity against\nrifampin-resistant mutants of Chlamydia pneumoniae","volume":"61","author":"Rothstein","year":"2008","journal-title":"J. Antibiot."},{"issue":"3","key":"2026090216342115800_cit25","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1099\/13500872-142-3-667","article-title":"The rRNA operons of Mycobacterium smegmatis and Mycobacterium\ntuberculosis: comparison of promoter elements and of neighbouring\nupstream genes","volume":"142","author":"Gonzalez-y-Merchand","year":"1996","journal-title":"Microbiology"},{"key":"2026090216342115800_cit26","doi-asserted-by":"publisher","first-page":"329ra32","DOI":"10.1126\/scitranslmed.aad7364","article-title":"TarO-specific\ninhibitors of wall teichoic acid biosynthesis restore beta-lactam\nefficacy against methicillin-resistant staphylococci","volume":"8","author":"Lee","year":"2016","journal-title":"Sci. Transl. Med."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.0c00223","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/9\/2431\/67004612\/acsinfecdis.0c00223.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/9\/2431\/67004612\/acsinfecdis.0c00223.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:34:28Z","timestamp":1788381268000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/9\/2431\/1292363\/A-Semisynthetic-Kanglemycin-Shows-In-Vivo-Efficacy"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,10]]},"references-count":26,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,8,10]]},"published-print":{"date-parts":[[2020,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.0c00223","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,10]]}}}