Efficacy of the New Lantibiotic NAI-107 in Experimental Infections Induced by Multidrug-Resistant Gram-Positive Pathogens

Abstract

NAI-107 is a novel lantibiotic active againstIn the granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log 10 -CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observed in vitro was thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

Antibiotic discovery in the twenty-first century: current trends and future perspectives

“…It is currently a developmental candidate for the treatment of nosocomial infections by Gram-positive pathogens. 40 The same screening program led to the identification of additional class I lantibiotics from actinomycetes. Among them, the compound 97518 (Figure 2a), structurally related to NAI-107, 41 afforded improved derivatives by chemical modification.…”

The Lantibiotic NAI-107 Binds to Bactoprenol-bound Cell Wall Precursors and Impairs Membrane Functions

“…NAI-107 is produced as a complex of two major structurally related 24-amino acid variants (A1, 2246 Da; and A2, 2230 Da), which differ in proline 14 being monohydroxylated in variant A2, or bishydroxylated in variant A1 (28). Overall NAI-107 seems to combine two known lipid II targeting motifs ( Fig.…”

“…resistant mutants were not observed during these studies. Preliminary mode of action studies gave the first hints toward inhibition of cell wall biosynthesis (28). In the present study, we set out to identify the molecular target and the specific mechanism of action of the lantibiotic NAI-107.…”

The antibiotic planosporicin coordinates its own production in the actinomycete Planomonospora alba

“…Although actinomycetes have not generally been recognized as prolific producers of potentially useful lantibiotics, two actinomycete compounds, NVB302 [an actagardine derivative (9)] and NAI-107 [also known as microbisporicin (10)] are currently in clinical development as anti-infectives, whereas a third, Moli1901 (also known as lancovutide or duramycin, a structural analog of cinnamycin), promises to be a useful adjunct for the treatment of cystic fibrosis (11,12). Actinomycete RiPPs that have been analyzed genetically include cinnamycin (13), the spore-associated proteins SapB (14) and SapT (15), michiganin (16), actagardine (17), deoxyactagardine (18), microbisporicin (19,20), cypemycin (21), venezuelin (22), and grisemycin (23).…”