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This study demonstrates that synergistic effects extend beyond the traditional one \u03b2-lactam + one BLI paradigm, refuting the oversimplified mechanistic framework. First, \u03b2-lactam-based BLIs such as clavulanic acid, sulbactam, and tazobactam exhibit intrinsic antibacterial activity against\n                      <jats:italic toggle=\"yes\">Mab<\/jats:italic>\n                      . These agents synergized not only with \u03b2-lactams but also with one another, undermining their historical classification as mere \u03b2-lactamase inhibitors. The data indicate that their activity is not limited to inhibiting \u03b2-lactamases but extends to directly targeting critical bacterial processes. Second, dual \u03b2-lactam combinations exhibit synergism against\n                      <jats:italic toggle=\"yes\">Mab<\/jats:italic>\n                      even in the absence of BLIs. For example, despite being rapidly hydrolyzed by the native \u03b2-lactamase Bla\n                      <jats:sub>Mab<\/jats:sub>\n                      , amoxicillin demonstrates strong synergism with \u03b2-lactams such as imipenem or ceftaroline. This suggests that the second \u03b2-lactam either acts as a functional BLI surrogate or targets complementary pathways. Supporting this, experiments using penicillin- and carbapenem-based probes revealed that \u03b2-lactams bind to multiple\n                      <jats:italic toggle=\"yes\">Mab<\/jats:italic>\n                      proteins simultaneously, reinforcing the idea that their synergy arises from targeting complementary essential proteins. Finally, triple combinations comprising dual \u03b2-lactam and one BLI, such as amoxicillin + ceftaroline + avibactam, achieved very high synergy, underscoring the complementary roles of dual \u03b2-lactams and BLIs. The evidence in this study necessitates a revised model that can more accurately explain the activities of \u03b2-lactams and BLIs and underscores the potential for optimizing \u03b2-lactam\/BLI regimens against\n                      <jats:italic toggle=\"yes\">Mab<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00127-25","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T14:21:21Z","timestamp":1755181281000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Combinations comprising dual \u03b2-lactams and a \u03b2-lactamase inhibitor achieve optimal synergistic inhibition of\n                    <i>Mycobacterium abscessus<\/i>\n                    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