In Vitro and Intracellular Activities of Peptide Deformylase Inhibitor GSK1322322 against Legionella pneumophila Isolates

Abstract

b GSK1322322, a novel peptide deformylase inhibitor currently in development as an oral and intravenous agent for the treatment of hospitalized community-acquired bacterial pneumonia, showed poor in vitro activity against a panel of 50 Legionella pneumophila strains, with MICs ranging from 1 to 16 g/ml and an MIC 90 of 16 g/ml, but very potent intracellular activity, with the minimum extracellular concentrations capable of inhibiting intracellular proliferation (MIECs) ranging from 0.12 to 2 g/ml and 98% of the strains being inhibited by concentrations of <1 g/ml.T he opportunistic Gram-negative bacterium Legionella pneumophila, which can grow free living or as a facultative intracellular organism in amoebae or human alveolar macrophages, is the major causative agent of Legionnaires' disease, a severe form of pneumonia (1). Although at least 15 serogroups have been identified, L. pneumophila serogroup 1 accounts for more than 80% of the cases worldwide (2). Except in the event of a Legionnaires' disease outbreak, L. pneumophila is treated empirically as part of the therapy used for hospitalized pneumonia, and given the severity of the disease, it is important to ensure that the antibacterial agent to be utilized shows good activity against this pathogen. GSK1322322 is a novel peptide deformylase (PDF) inhibitor with good safety and pharmacokinetic properties (3-5) and is currently in phase II development as an oral and intravenous agent for the treatment of hospitalized community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. GSK1322322 has demonstrated good antibacterial activity against other causative agents of bacterial pneumonia, such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae (6), so it was therefore important to investigate its potency against this atypical pathogen.In order to assess the in vitro activity of GSK1322322, we performed susceptibility studies against 50 L. pneumophila strains: 25 from serogroup 1 and 5 each from serogroups 2, 3, 4, 5, and 6. L. pneumophila isolates were collected from 1992 to 2013, mostly from the human respiratory tract, and grown on buffered charcoal yeast extract (BCYE) agar to produce pure cultures. MIC endpoints were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines (7). MIC plates, containing approximately 5 ϫ 10 5 CFU/ml in buffered yeast extract (BYE) broth (with Legionella BCYE growth supplement), were incubated at 35°C in aerobic conditions for 48 h. The MIC was defined as the lowest concentration of antimicrobial agent that completely inhibited visible growth after the appropriate incubation time.GSK1322322 showed variable activities against this panel of 50 L. pneumophila strains, with MICs ranging from 1 to 16 g/ml and MIC 50 and MIC 90 values of 8 and 16 g/ml, respectively (Table 1). No significant differences were observed in the activities of GSK1322322 against strains from different serogroups; 8 g/ml was the most frequent MIC ...

Marine Peptide-N6NH2 and Its Derivative-GUON6NH2 Have Potent Antimicrobial Activity Against Intracellular Edwardsiella tarda in vitro and in vivo

“…Based on the advantages of broad-spectrum activity, rapid killing rate and low drug resistance, antimicrobial peptides (AMPs) open a new way for the development of antimicrobial agents ( Czaplewski et al, 2016 ). It has been demonstrated that some AMPs such as cathelicidin ( Sonawane et al, 2011 ), GSK1322322 ( Dubois et al, 2015 ), plectasin derivatives-MP1102/NZ2114/H2 ( Brinch et al, 2010 ; Wang X. et al, 2018 , 2019 ), and temporins ( Crepin et al, 2020 ) exhibit potent intracellular activity against Mycobacterium tuberculosis , Legionella pneumophila , methicillin-susceptible/-resistant Staphylococcus aureus , and Legionella pneumophila , respectively. A marine peptide-NZ17074 (N1) is a variant of arenicin-3 (Tyr5→Asn, Tyr17→His) isolated from marine lugworm Arenicola marina and has strong intracellular antibacterial activity against Gram-negative bacteria (including Escherichia coli , Salmonella , Pseudomonas aeruginosa , etc.)…”

Effect of Food on the Bioavailability of Omadacycline in Healthy Participants

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