{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:05:01Z","timestamp":1790867101949,"version":"4.1.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      The overexpression of efflux pumps (Eps) was reported to contribute to multidrug resistant\n                      <jats:italic toggle=\"yes\">tuberculosis<\/jats:italic>\n                      (MDR-TB). Increases in Eps that expel structurally unrelated drugs contribute to reduced susceptibility by decreasing the intracellular concentration of antibiotics. In the present study, an association of mycobacterial membrane protein (MmpS5-MmpL5) Ep and its gene regulator (\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0678) was investigated in MDR-tuberculosis isolates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      MTB strains were isolated from patients at two different intervals, i.e., once when they had persistent symptoms despite 3\u201315 \u2265 months of treatment and once when they had started new combination therapy \u22652\u20133 months. Sputum specimens were subjected to Xpert MTB\/rifampicin test and then further susceptibility testing using proportional method and multiplex polymerase chain reaction (PCR) were performed on them. The isolates were characterized using both 16S-23S RNA and\n                      <jats:italic toggle=\"yes\">hsp<\/jats:italic>\n                      65 genes spacer (PCR-restriction fragment length polymorphism). Whole-genome sequencing (WGS) was investigated on two isolates from culture-positive specimen per patient. The protein structure was simulated using the SWISS-MODEL. The input format used for this web server was FASTA (amino acid sequence). Protein structure was also analysis using Ramachandran plot\n                      <jats:italic toggle=\"yes\"\/>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      WGS documented deletion, insertion, and substitution in transmembrane transport protein MmpL5 (\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0676) of Eps. Majority of the studied isolates (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 12; 92.3%) showed a unique deletion mutation at three positions: (a) from amino acid number 771 (isoleucine) to 776 (valine), (b) from amino acid number 785 (valine) to 793 (histidine), and (c) from amino acid number 798 (leucine) to 806 (glycine).\u201d One isolate (7.6%) had no deletion mutation. In all isolates (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 13; 100%), a large insertion mutation consisting of 94 amino acid was observed \u201cfrom amino acid number 846 (isoleucine) to amino acid number 939 (leucine)\u201d. Thirty-eight substitutions in\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0676 were detected, of which 92.3% were identical in the studied isolates. WGS of mycobacterial membrane proteins (MmpS5;\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0677) and its gene regulator (\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0678) documented no deletion, insertion, and substitution. No differences were observed between MmpS5-MmpL5 and its gene regulator in isolates that were collected at different intervals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Significant genetic mutation like insertion, deletion, and substitution within transmembrane transport protein MmpL5 (\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0676) can change the functional balance of Eps and cause a reduction in drug susceptibility. This is the first report documenting a unique amino acid mutation (insertion and deletion \u22654\u201394) in\n                      <jats:italic toggle=\"yes\">Rv<\/jats:italic>\n                      0676 among drug-resistant MTB. We suggest the changes in Mmpl5 (\n                      <jats:italic toggle=\"yes\">Rv0676<\/jats:italic>\n                      ) might occurred due to in-vivo sub-therapeutic drug stress within the host cell. Changes in MmpL5 are stable and detected through subsequent culture-positive specimens.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/ijmy.ijmy_37_24","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T20:00:06Z","timestamp":1710878406000},"page":"7-14","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":10,"title":["The Role of Efflux Pumps transporter in Multi-drug Resistant Tuberculosis: Mycobacterial memberane protein(MmpL5)"],"prefix":"10.4103","volume":"13","author":[{"given":"Parissa","family":"Farnia","sequence":"first","affiliation":[{"name":"Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Tehran, 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