MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N-H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.
"MK-7655, a novel DBO that is structurally similar to AVI except for an additional piperidine ring, exhibits synergy in combination with imipenem against KPC-producing K. pneumoniae and P. aeruginosa expressing AmpC (Figure 2; Mangion et al., 2011; Hirsch et al., 2012). Studies show that at a concentration of 4 mg/L, MK-7655 lowers imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16–64 mg/L to 0.12–1 mg/L (Livermore et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: The increasing incidence and prevalence of multi-drug resistance (MDR) among contemporary Gram-negative bacteria represents a significant threat to human health. Since their discovery, β-lactam antibiotics have been a major component of the armamentarium against these serious pathogens. Unfortunately, a wide range of β-lactamase enzymes have emerged that are capable of inactivating these powerful drugs. In the past 30 years, a major advancement in the battle against microbes has been the development of β-lactamase inhibitors, which restore the efficacy of β-lactam antibiotics (e.g., ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin/clavulanate, and piperacillin/tazobactam). Unfortunately, many newly discovered β-lactamases are not inactivated by currently available inhibitors. Is there hope? For the first time in many years, we can anticipate the development and introduction into clinical practice of novel inhibitors. Although these inhibitors may still not be effective for all β-lactamases, their introduction is still welcome. This review focuses on the novel β-lactamase inhibitors that are closest to being introduced in the clinic.
Frontiers in Microbiology 12/2013; 4:392. DOI:10.3389/fmicb.2013.00392 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the antibiotic drug development pipeline, especially those with new modes of action, is a major health concern. This review lists the 20 new antibiotics launched since 2000 and records the 40 compounds currently in active clinical development. Compounds in the pipeline from new antibiotic classes are reviewed in detail with reference to their development status, mode of action, spectrum of activity and lead discovery. In addition, the NP or synthetic derivation is discussed, with activity against Gram-negative bacteria highlighted.
The Journal of Antibiotics 06/2011; 64(6):413-25. DOI:10.1038/ja.2011.44 · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: beta-Lactam antibiotics are one of the most important antibiotic classes but are plagued by problems of resistance and the development of new beta-lactam antibiotics through side chain modification of existing beta-lactam classes is not keeping pace with resistance development. In this perspective we summarize small molecule strategies to overcome resistance to beta-lactam antibiotics. These approaches include the development of beta-lactamase inhibitors and compounds that interfere with the ability of the bacteria to sense an antibiotic threat and activate their resistance mechanisms.
The Journal of Organic Chemistry 03/2013; 78(9). DOI:10.1021/jo400236f · 4.72 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.