Stefan Nicolet

Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication

Lens epithelium-derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase that promotes viral integration by tethering the preintegration complex to the chromatin. By virtue of its crucial role in the early steps of HIV replication, the interaction between LEDGF/p75 and integrase represents an attractive target for antiviral therapy. We have rationally designed a series of 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs) that act as potent inhibitors of the LEDGF/p75-integrase interaction and HIV-1 replication at submicromolar concentration by blocking the integration step. A 1.84-A resolution crystal structure corroborates the binding of the inhibitor in the LEDGF/p75-binding pocket of integrase. Together with the lack of cross-resistance with two clinical integrase inhibitors, these findings define the 2-(quinolin-3-yl)acetic acid derivatives as the first genuine allosteric HIV-1 integrase inhibitors. Our work demonstrates the feasibility of rational design of small molecules inhibiting the protein-protein interaction between a viral protein and a cellular host factor.

Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibiotic drug design.

The development of resistance to virtually all current antibiotics makes the discovery of new antimicrobial compounds with novel protein targets an urgent challenge. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is an essential metallo-enzyme for growth and proliferation in many bacteria, acting in the desuccinylation of N-succinyl-L,L-diaminopimelic acid (SDAP) in a late stage of the anabolic pathway towards both lysine and a crucial building block of the peptidoglycan cell wall. L-Captopril, which has been shown to exhibit very promising inhibitory activity in vitro against DapE and has attractive drug-like properties, nevertheless does not target DapE in bacteria effectively. Here we show that L-captopril targets only the Zn(2+)-metallo-isoform of the enzyme, whereas the Mn(2+)-enzyme, which is also a physiologically relevant isoform in bacteria, is not inhibited. Our finding provides a rationale for the failure of this promising lead-compound to exhibit any significant antibiotic activity in bacteria and underlines the importance of addressing metallo-isoform heterogeneity in future drug design. Moreover, to our knowledge, this is the first example of metallo-isoform heterogeneity in vivo that provides an evolutionary advantage to bacteria upon drug-challenge.

Plasmid-mediated colistin resistance in a patient infected with Klebsiella pneumoniae

998 www.thelancet.com/infection Vol 16 September 2016 (98·7%) of the mMITT population had at least one such pathogen confirmed as multidrug resistant (resistant to at least three categories of antimicrobials, as defined by Magiorakos and colleagues), with most producing extended-spectrum β lactamases. Three patients in each treatment group had Klebsiella pneumoniae carba penemase-pro ducing isolates, and three patients (two on ceftazidime-avibactam and one on best available therapy) had an OXA-48 producer. Four patients on ceftazidime-avibactam and two on best available therapy had metalloβ-lactamase-producing isolates; avibactam has no inhibitory eff ect on class B metallo-β-lactamases. With the exception of eight patients with P aeruginosa that were non-metalloβ-lactamase producers, and had a ceftazidime-avibactam minimum inhibitory concentration of more than 8 mg/L, all of the other nonmetallo-β-lactamase producers had ceftazidime-avibactam minimum inhibitory concentrations of less than or equal to 8 mg/L (in the provisional susceptible range).