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In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against\n                    <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n                    , including multidrug-resistant (MDR) metallo-\u03b2-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal \u03b2-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (\n                    <jats:italic>mexR<\/jats:italic>\n                    ), porin-deficient (\n                    <jats:italic>oprD<\/jats:italic>\n                    ), and AmpC-hyperproducing (\n                    <jats:italic>dacB<\/jats:italic>\n                    ) derivatives of PAO1, and MBL-expressing clinical strains ST175 (\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>VIM-2<\/jats:sub>\n                    ) and ST111 (\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>VIM-1<\/jats:sub>\n                    ). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    [\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    <jats:sub>app<\/jats:sub>\n                    ] &gt; 100 \u03bcM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 \u03bcg\/ml (amdinocillin MICs &gt; 32 \u03bcg\/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 \u03bcg\/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested \u03b2-lactams for each of the\n                    <jats:named-content content-type=\"genus-species\">P. aeruginosa<\/jats:named-content>\n                    mutant strains. Likewise, antipseudomonal \u03b2-lactams (CLSI breakpoints), in combination with 4 or 8 \u03bcg\/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. \u03b2-Lactam\u2013WCK enhancer combinations represent a promising \u03b2-lactam \u201cenhancer-based\u201d approach to treat MDR\n                    <jats:named-content content-type=\"genus-species\">P. aeruginosa<\/jats:named-content>\n                    infections, bypassing the need for MBL inhibition.\n                  <\/jats:p>","DOI":"10.1128\/aac.02529-16","type":"journal-article","created":{"date-parts":[[2017,3,13]],"date-time":"2017-03-13T20:42:27Z","timestamp":1489437747000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":140,"title":["WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent \u201c\u03b2-Lactam Enhancer\u201d Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-\u03b2-Lactamase-Producing High-Risk Clones"],"prefix":"10.1128","volume":"61","author":[{"given":"Bartolome","family":"Moya","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma, Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel M.","family":"Barcelo","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma, Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Bhagwat","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre, Aurangabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Patel","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre, Aurangabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Bou","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Complejo Hospitalario Universitario A Coru\u00f1a, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina M.","family":"Papp-Wallace","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA"},{"name":"Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"},{"name":"Departments of Pharmacology, Molecular Biology and Microbiology, and Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Oliver","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma, Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhin.2009.04.020"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1592\/phco.2005.25.10.1353"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2005.01161.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00040-09"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1086\/338782"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.4103\/0974-777X.176142"},{"key":"e_1_3_2_8_2","first-page":"922","article-title":"Prevalence of multi and pan drug resistant Pseudomonas aeruginosa with respect to ESBL and MBL in a tertiary care hospital","volume":"50","author":"Jayakumar S","year":"2007","unstructured":"Jayakumar S AppalarajuB. 2007. 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