OP0595 acts in three ways: (i) as an inhibitor of class A and C β-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an 'enhancer' of β-lactam agents that bind to other PBPs besides PBP2 for several Enterobacteriaceae. OP0595 has considerable potential to overcome resistance when it is combined with various β-lactam agents.

We report the enantioselective total synthesis of cribrostatin IV (1). Key features of this synthesis involve the convergent coupling of two highly functionalized homochiral components followed by a "lynchpin" Mannich cyclization to establish the pentacyclic core (cf. 19 --> 20).

A new strategy was designed for the construction of the pentacyclic ring system of ecteinascidin 743. Key features include highly concise routes to the enantiopure, configurationally matched subunit 1, a novel vinylogous Pictet–Spengler cyclization to 2, and a stereospecific epoxidation and regioselective reduction sequence of the C3C4 enamide to secure 3.

Gram-negative bacteria are evolving to produce ␤-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine ␤-lactamase inhibitor which acts also as an antibiotic and as a ␤-lactamase-independent ␤-lactam "enhancer" against Enterobacteriaceae. Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, in in vitro time-kill studies and an in vivo infection model against five strains of CTX-M-15-positive Escherichia coli and five strains of KPC-positive Klebsiella pneumoniae. An OP0595 concentration of 4 g/ml was found to be sufficient for an effective combination with all three ␤-lactam agents. In both in vitro time-kill studies and an in vivo model of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all ␤-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a ␤-lactam agent is important to exert the antimicrobial functions of OP0595.T he global increase in antibiotic-resistant Gram-negative bacteria in recent years is posing a serious medical problem. In many cases, the mechanism underlying bacterial resistance involves the production of ␤-lactamase. As of 2012, roughly 1,300 ␤-lactamases had been identified, including many that are not inhibited by established ␤-lactamase inhibitors such as tazobactam and clavulanic acid and several that hydrolyze carbapenems, which were previously regarded as "␤-lactamase stable" (1).␤-Lactamases can be classified according to several schemes. The most fundamental one is the Ambler classification, which is based on amino acid sequence and subdivides the serine ␤-lactamases into class A, including the common TEM, SHV, CTX-M, and KPC types, class C (e.g., AmpC, CMY, etc.), and class D (OXA). Class B comprises metalloenzymes (e.g., IMP, NDM, etc.) that require divalent cations, generally zinc, for substrate hydrolysis (2).The spread of extended-spectrum TEM, SHV, and CTX-M ␤-lactamases has led to increased clinical dependence on carbapenems; however, carbapenemase-producing Enterobacteriaceae spp. are spreading rapidly worldwide (3). The most prevalent types of carbapenemase vary geographically; for example, KPC types are dominant in North and South America, China, Israel, and parts of southern Europe, whereas OXA-48 is prevalent in the Middle East (except Israel) and NDM is common in south Asia (4). Bacteria expressing these enzymes can cause severe infections, and the fatality rate in cases of bloodstream infections involving carbapenemase-producing Klebsiella pneumoniae is high (5).As a result, new and effective ␤-lactamase inhibitors are urgently needed, and diazabicyclooctanes such as avibactam, relebactam (MK-7655), and OP0595 are under clinical development for this role (6, 7). Diazabicyclooctanes represent a new class of ␤-lactamase ...