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However, the continued emergence and spread of metallo-\u03b2-lactamases (MBLs), for which no clinically approved inhibitors currently exist, poses a serious threat to the long-term effectiveness of \u03b2-lactam-based therapies. To bridge this therapeutic gap, the boronic acid transition state analog, taniborbactam (Venatorx Pharmaceuticals), was developed, targeting SBLs and widespread MBLs such as NDM-1 and VIM-2. However, taniborbactam-escape variants have been detected among various MBL enzymes, including members of the NDM and IMP families. Here, we explored whether covalently combining two complementary inhibitor structures, a boronic acid transition state analog and a dipicolyl ethylenediamine-based metal chelator, can restore \u03b2-lactam susceptibility in MBL-producing bacterial strains, including taniborbactam-escape variants. APC24-7 successfully sensitized clinical isolates of SBL- and MBL-producing\n                      <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      to meropenem. While APC24-7 demonstrated similarities in resensitization behavior to taniborbactam against a wide range of isogenic\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      expressing single SBLs, APC24-7 reversed NDM-9- or IMP-26-mediated meropenem resistance more efficiently. To investigate the potential role of the chelator motif in the MBL inhibition of APC24-7, susceptibility tests were conducted with an excess of exogenous Zn\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      . APC24-7-mediated resensitization remained unaffected in the presence of Zn\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      for strains producing NDM-1 and VIM-2. However, its ability to reverse NDM-9- and IMP-26-mediated meropenem resistance was attenuated upon Zn\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      supplementation. These findings demonstrate that combining functionally complementary chemical structures, such as chelators and boronic acids, can aid in expanding the resensitization ability of existing \u03b2-lactamase inhibitors.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The ability of bacteria such as\n                        <jats:italic toggle=\"yes\">Klebsiella pneumoniae<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                        to circumvent antimicrobial chemotherapy has become a global public health crisis. The high prevalence of \u03b2-lactamase enzymes capable of rendering our most prescribed antibiotics, the \u03b2-lactams (BLs) inactive, has left us with few available treatment options against infections caused by these bacteria. The use of small molecules that inhibit especially serine \u03b2-lactamases has substantially prolonged the lifetime of BL antibiotics. Yet, most clinically available inhibitors either do not possess or have limited ability to reverse resistance conferred by metallo-\u03b2-lactamase (MBL) enzymes. Combining chelator and transition state analog technology, our hybrid compound restores the effectiveness of BL antibiotics in cases of resistance conferred by both serine \u03b2-lactamases (SBLs) and MBLs. Our approach of covalently combining a chelator with an existing SBL inhibitor scaffold offers a promising solution for managing life-threatening infections and prolonging the use of clinically available BLs.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00418-25","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T14:00:27Z","timestamp":1764770427000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["APC24-7, a covalent combination of boronic acid and chelator moieties, restores \u03b2-lactam efficiency against metallo-\u03b2-lactamase-producers"],"prefix":"10.1128","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2087-9857","authenticated-orcid":true,"given":"Rebekka Rolfsnes","family":"Hovd","sequence":"first","affiliation":[{"name":"Adjutec Pharma","place":["Oslo, 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