Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of β-lactamases, enzymes that inactivate β-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new β-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine β-lactamase inhibitors that potently inhibit clinically relevant class A, C and D β-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of β-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam-ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.

Immune responses to foreign and selfAgs can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2R␣ chain (CD25). Defects in Tregs lead IntroductionBoth Ag-specific 1 and naive regulatory T cells (Tregs) 2-4 that control immune responses are mainly CD4 ϩ CD25 ϩ T cells 5 expressing transcription factor FOXP3. 6 Autoimmunity occurs with the breakdown in immune tolerance to self-Ag and can be because of a failure of natural Tregs (nTregs) produced by the thymus which prevent spontaneous autoimmune activation of CD4 ϩ CD25 Ϫ T effector cells by inhibiting APCs. 5 nTregs maintain immune homeostasis and are polyclonally expanded by IL-2. nTregs can suppress all immune responses, because they are not Ag specific. To fully suppress high ratios to effector lineage, CD4 ϩ CD25 Ϫ T cells are required, usually Ͼ 1:1; whereas the natural ratio of these cells in peripheral lymphoid tissues is tightly regulated to Ͻ 1:10. 7,8 There is ample evidence for Ag-specific Treg induction in vivo, including T-cell transfer of tolerance to specific autoantigen induced by immunization with autoantigen without complete Freund adjuvant (CFA), 9 the parabiosis of tolerance to autoimmunity from normal hosts, 10 and the epitope specificity of tolerance induction with an autoantigen. 11 Ag-specific CD4 ϩ CD25 ϩ Tregs have phenotypic and functional differences from the nTreg, recently reviewed by Hall et al. 12 Activated Tregs do not migrate from blood to lymph but express chemokine receptors and other ligands that promote their migration to sites of inflammation, where they control local inflammation. 12 Further, their action is not to inhibit APCs via CTLA4, but to inhibit or eliminate activated effector T cells and macrophages, by a variety of mechanisms. 12 To date, most studies focused on nTregs that suppress in a non-Ag-specific manner and must be present at high ratios with effector T cells to fully suppress an immune response. In autoimmune disease it would be desirable to induce Ag-specific Tregs that can suppress only the specific immune response at low ratios (Ͻ 1:10) to effector cells. 13 Specific immune tolerance, as occurs in adult rodents that accept an allograft long term, is mediated by Ag-specific CD4 ϩ CD25 ϩ Tregs that suppress at ratios Ͻ 1:10. 1,14,15 These alloantigen-specific Tregs are difficult to identify, because their survival depends on stimulation by both Ag 1,16 and T cell-derived cytokines. 17 IL-2 17 or IL-4 do not fully maintain activated Agspecific Tregs, but other cytokines such as IL-5 can. 3 In our studies, the initial activation of nTregs to alloantigenspecific Tregs occurred when they were cultured with specific alloantigens and either the T helper type 1 (Th1) cytokine IL-2 or the Th2 cytokine IL-4, but not other Th1 or Th2 cytokines. 3 Alloactivation of nTregs with IL-2 induces the receptor for the late Th1 cytokine IFN-␥ (Ifn␥r) but not the receptor for the Th2 cytokine ␤, Ifn␥r. 3 The selective induction of Il-5r␣ on Ag-activated Tregs that have been stimulated by IL-4, not IL-2, ra...

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Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward β-lactam antibiotics. The hydrolytic enzymes called β-lactamases are responsible for a large proportion of the resistance phenotype. β-Lactamase inhibitors (BLIs) can be administered in combination with β-lactam antibiotics to negate the action of the β-lactamases, thereby restoring activity of the β-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) β-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon–carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine β-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.

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