{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T15:27:08Z","timestamp":1767626828931},"reference-count":55,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2016,6,20]],"date-time":"2016-06-20T00:00:00Z","timestamp":1466380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,7,1]],"date-time":"2016-07-01T00:00:00Z","timestamp":1467331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The evolution of multiple-antibiotic-resistant bacteria is an increasing global problem. Even though mutations causing resistance usually incur a fitness cost in the absence of antibiotics, the magnitude of such costs varies across environments and genomic backgrounds. We studied how the combination of mutations that confer resistance to rifampin (Rif\n            <jats:sup>r<\/jats:sup>\n            ) and streptomycin (Str\n            <jats:sup>r<\/jats:sup>\n            ) affects the fitness of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Escherichia coli<\/jats:named-content>\n            when it interacts with cells from the immune system, i.e., macrophages (M\u03d5s). We found that 13 Rif\n            <jats:sup>r<\/jats:sup>\n            Str\n            <jats:sup>r<\/jats:sup>\n            doubly resistant genotypes, of the 16 tested, show a survival advantage inside M\u03d5s, indicating that double resistance can be highly beneficial in this environment. Our results suggest that there are multiple paths to acquire multiple-drug resistance in this context, i.e., if a clone carrying Rif\n            <jats:sup>r<\/jats:sup>\n            allele H526 or S531 acquires a second mutation conferring Str\n            <jats:sup>r<\/jats:sup>\n            , the resulting double mutant has a high probability of showing increased survival inside M\u03d5s. On the other hand, we found two cases of sign epistasis between mutations, leading to a significant decrease in bacterial survival. Remarkably, infection of M\u03d5s with one of these combinations, K88R+H526Y, resulted in an altered pattern of gene expression in the infected M\u03d5s. This indicates that the fitness effects of resistance may depend on the pattern of gene expression of infected host cells. Notwithstanding the benefits of resistance found inside M\u03d5s, the Rif\n            <jats:sup>r<\/jats:sup>\n            Str\n            <jats:sup>r<\/jats:sup>\n            mutants have massive fitness costs when the bacteria divide outside M\u03d5s, indicating that the maintenance of double resistance may depend on the time spent within and outside phagocytic cells.\n          <\/jats:p>","DOI":"10.1128\/aac.00624-16","type":"journal-article","created":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T03:05:16Z","timestamp":1462849516000},"page":"4324-4332","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Enhanced Survival of Rifampin- and Streptomycin-Resistant Escherichia coli Inside Macrophages"],"prefix":"10.1128","volume":"60","author":[{"given":"Paulo","family":"Dur\u00e3o","sequence":"first","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]},{"given":"Daniela","family":"G\u00fclere\u015fi","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]},{"given":"Jo\u00e3o","family":"Proen\u00e7a","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]},{"given":"Isabel","family":"Gordo","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.293.5536.1786"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000578"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000406"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124410"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1369-5274(99)00005-3"},{"key":"e_1_3_3_7_2","first-page":"265","article-title":"Bacterial evolution and the cost of antibiotic resistance","volume":"1","author":"Lenski RE","year":"1998","unstructured":"Lenski RE. 1998. Bacterial evolution and the cost of antibiotic resistance. Int Microbiol 1:265\u2013270.","journal-title":"Int Microbiol"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2319"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5457.1479"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05685"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2014.17"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/emph\/eot003"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.2011.01302.x"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msv143"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2298"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00710-10"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470600122.ch14"},{"key":"e_1_3_3_18_2","first-page":"182","article-title":"Escherichia coli pyomyositis in an immunocompromised host","volume":"110","author":"Sharma U","year":"2011","unstructured":"Sharma U, Schwan WR, Agger WA. 2011. Escherichia coli pyomyositis in an immunocompromised host. WMJ 110:182\u2013184.","journal-title":"WMJ"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/tid.12046"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0b013e31819dd0cf"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01632-12"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.2012.01722.x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.110.123083"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1420-9101.2009.01712.x"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb0117s79"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg867"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.1.125-132.2000"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00128.2004"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003802"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1129"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.04649.x"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002107"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/jobm.200900124"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.4014\/jmb.1005.05019"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1556\/AMicr.59.2012.1.8"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.2.3.136"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4588.1009"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00425-06"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.32.4.1095-1098.1994"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.41.5.2209-2212.2003"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aab1621"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221552110"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.06.046"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10072"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.07.007"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005121"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2048"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00077"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1684"},{"key":"e_1_3_3_50_2","first-page":"307","volume-title":"Cytokine reference: a compendium of cytokines and other mediators of host defense","author":"Dinarello CA","year":"2001","unstructured":"Dinarello CA. 2001. IL-1\u03b1, p 307\u2013318. In Durum SK, Oppenheim JJ, Feldmann M (ed), Cytokine reference: a compendium of cytokines and other mediators of host defense. Academic Press, Inc., Boston, MA."},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2711"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12397"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.06.009"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(92)90466-W"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.18.5280"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(02)02305-3"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00624-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00624-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:37:15Z","timestamp":1645475835000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00624-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7]]},"references-count":55,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2016,7]]}},"alternative-id":["10.1128\/AAC.00624-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.00624-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7]]},"assertion":[{"value":"2016-03-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-06-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}