Article Figures & Data
Figures
- FIG 1
Chemical structure of NOSO-502.
- FIG 2
Bactericidal activity of NOSO-502 at 4× and 8× MIC against E. coli ATCC 25922 and K. pneumoniae ATCC 43816. Closed circles, drug-free control; closed squares, NOSO-502 at 4× MIC; closed triangles, NOSO-502 at 8× MIC. Experiments were performed in triplicate. Each symbol represents the mean, and error bars indicate the SEMs.
- FIG 3
Pharmacokinetic studies with CD-1 mice (closed squares) and Sprague-Dawley rats (closed circles) following intravenous dosing at 30 and 15 mg/kg, respectively. Each symbol represents the mean, and error bars indicate the SEMs.
- FIG 4
Efficacy of NOSO-502 and colistin in a neutropenic murine sepsis infection model against E. coli EN122. Each symbol represents an individual mouse, and the horizontal line indicates the mean. Error bars indicate the SEMs. Statistically significant reduction versus vehicle control (one-way analysis of variance [ANOVA], Dunnett's comparison) is indicated as follows: ns, not significant; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.
- FIG 5
Efficacy of NOSO-502 and ciprofloxacin in a murine UTI model against E. coli UTI89. Each symbol represents an individual mouse, and the horizontal line indicates the mean. Error bars indicate the SEMs. Statistically significant reduction versus vehicle control (Kruskal-Wallis statistical test, multiple comparison) is indicated as follows: ns, not significant; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.
- FIG 6
Efficacy of NOSO-502 and tigecycline in a survival neutropenic sepsis infection model against E. coli ATCC BAA-2469 (NDM-1). Each symbol represents an individual mouse, and the horizontal line indicates the mean. Error bars indicate the SEMs. Statistically significant reduction versus vehicle control (Kruskal-Wallis statistical test, multiple comparison) is indicated as follows: ns, not significant; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.
- FIG 7
Efficacy of NOSO-502 and tigecycline in a murine lung infection model against K. pneumoniae NCTC 13442 (OXA-48). Each symbol represents an individual mouse, and the horizontal line indicates the mean. Error bars indicate the SEMs. Statistically significant reduction versus vehicle control (one-way ANOVA, Dunnett's comparison) is indicated as follows: ns, not significant; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; ****, P ≤ 0.0001.
Tables
- TABLE 1
Bacterial susceptibility profile of NOSO-502 against reference bacterial strainsa
Strain MIC (μg/ml) of antibiotic NOS CIP GEN IPM TGC PMB Citrobacter freundii DSM 30039 2 ≤0.125 0.5 1 1 0.5 Citrobacter kozeri DSM 4595 2 ≤0.125 0.25 4 1 0.25 Enterobacter aerogenes DSM 30053 2 ≤0.125 0.25 2 1 0.5 Enterobacter cloacae DSM 14563 2 ≤0.125 0.5 1 4 1 Escherichia coli ATCC 25922 4 ≤0.125 1 0.25 0.25 0.5 Klebsiella pneumoniae ATCC 43816 1 ≤0.125 0.25 1 2 1 Serratia marcescens DSM 17174 4 ≤0.125 0.5 2 4 >32 Acinetobacter baumannii ATCC 19606 >64 2 16 0.5 1 0.5 Pseudomonas aeruginosa DSM 1117 >64 1 1 2 >8 1 Stenotrophomonas maltophilia ATCC 13637 16 1 4 >64 0.5 1 Enterococcus faecalis DSM 2570 >64 2 16 1 0.25 >32 Enterococcus faecium DSM 20477 64 16 8 4 0.125 >32 Staphylococcus aureus ATCC 29213 1 0.25 0.5 ≤0.125 0.5 16 Staphylococcus epidermidis ATCC 12228 0.25 0.25 ≤0.125 ≤0.125 0.5 16 Streptococcus pneumoniae DSM 2134 64 1 8 ≤0.125 0.125 >32 ↵a NOS, NOSO-502; CIP, ciprofloxacin; GEN, gentamicin; PMB, polymyxin B; IPM, imipenem; TGC, tigecycline.
- TABLE 2
MICs of NOSO-502 and comparators against a panel of recent clinical bacterial strainsa
Organism (no. of isolates) Antibiotic MIC (μg/ml) Range 50% 90% Citrobacter freundii (16) NOS 1–4 2 2 CIP 0.008–>1 0.03 >1 GEN 0.5–>32 1 >32 PMB 0.25–1 0.5 1 Enterobacter cloacae (13) NOS 1–4 1 2 CIP 0.016–>1 >1 >1 GEN 1–>32 32 >32 PMB 0.5–16 0.5 8 Escherichia coli (101) NOS 2–32 4 8 CIP 0.008–>1 0.03 >1 GEN 0.5–>32 1 2 PMB 0.25–32 0.5 1 Ciprofloxacin-resistant E. coli (19) NOS 2–32 4 8 CIP >1 >1 >1 GEN 0.13–>32 0.5 >32 PMB 0.5–32 0.5 1 Gentamicin-resistant E. coli (6) NOS 4 CIP 0.25–1 GEN 32–>32 PMB 0.25–32 Polymyxin B-resistant E. coli (2) NOS 4–8 CIP 1–>1 GEN 1–>32 PMB 4–32 Klebsiella pneumoniae (56) NOS 0.5–16 1 2 CIP 0.008–>1 0.5 >1 GEN 0.5–>32 1 >32 PMB 0.25–32 0.5 4 Ciprofloxacin-resistant K. pneumoniae (27) NOS 0.5–16 1 2 CIP >1 >1 >1 GEN 0.13–>32 32 >32 PMB 0.5–>32 0.5 1 Gentamicin-resistant K. pneumoniae (16) NOS 0.5–2 1 2 CIP 0.5–>1 >1 >1 GEN 32–>32 >32 >32 PMB 0.5–1 0.5 1 ↵a MIC50 and MIC90 were calculated for populations with >10 isolates.
- TABLE 3
Activities of NOSO-502 and comparators against carbapenem-resistant Enterobacteriaceae strains
Type of enzyme or organism and strain β-Lactamase content MIC (μg/ml) of antibiotic NOS CIP GEN IPM TGC PMB Ambler class A carbapenemase Escherichia coli PSP KPC-2 + TEM-1 + OXA-1 2 16 >64 8 0.5 0.5 Escherichia coli COL KPC-2 + TEM-1 + CTX-M9 2 >64 >64 8 0.5 0.5 Escherichia coli MIN KPC-3 + OXA-9 4 <0.25 0.5 8 0.25 0.5 Klebsiella pneumoniae ATCC BAA-1905 KPC-2 1 >64 32 >64 4 0.5 Klebsiella pneumoniae A33504 KPC-2+ SHV-11 + TEM-1 + CTX-M-2 + OXA-9 1 32 >64 16 2 0.5 Klebsiella pneumoniae ATCC BAA-1904 KPC-3 2 0.25 16 32 2 0.5 Enterobacter cloacae KBM15 KPC-2 + TEM-1 + OXA-9 1 32 8 32 8 0.5 Ambler class B carbapenemase Escherichia coli BAA-2469 NDM-1 2 16 >64 32 1 0.25 Escherichia coli BAA-2471 NDM-1 4 >64 >64 >64 1 0.25 Escherichia coli MON NDM-5 + CTX-M15 + TEM-1 4 >64 0.5 32 0.5 0.5 Escherichia coli GAL NDM-6 + OXA-1 + CTX-M15 2 >64 2 32 0.5 0.25 Escherichia coli EGB957 VIM-1 + OXA-48 + TEM-1 + CMY-4 + OXA-1 4 >64 >64 >64 1 0.5 Klebsiella pneumoniae ATCC BAA-2146 NDM-1 + CTX-M15 + TEM-1 + CMY-6 + OXA-1 + SHV-1 0.5 >64 >64 >64 32 1 Klebsiella pneumoniae NCTC 13443 NDM-1 1 >64 >64 >64 4 0.5 Klebsiella pneumoniae LAM NDM-4 + SHV-11 + CTX-M15 1 >64 >64 32 2 0.5 Klebsiella pneumoniae NCTC 13439 VIM-1 1 16 1 32 2 0.5 Enterobacter cloacae 3047 NDM-1 + CTX-M15 + TEM-1 + OXA-1 1 2 32 16 4 0.5 Ambler class C carbapenem resistant Enterobacter cloacae 10.72 AmpC overexpressed + TEM-1 + OXA-1 1 >64 >64 4 8 0.5 Citrobacter freundii MAU AmpC overexpressed + TEM-3 1 >64 2 4 8 0.5 Ambler class D carbapenemase Escherichia coli DOV OXA-48 + TEM-1 + CTX-M15 + OXA-1 2 >64 32 4 2 0.5 Klebsiella pneumoniae NCTC 13442 OXA-48 1 4 0.25 16 2 0.5 Klebsiella pneumoniae DUB OXA-48 + CTX-M15 + TEM-1 + SHV-1 + OXA-1 + CMY-2 0.5 >64 >64 16 4 0.5 Enterobacter cloacae YAM OXA-48 + CTX-M15 + TEM-1 + OXA-1 + DHA-1 2 >64 >64 4 4 1 Enterobacter cloacae BEU OXA-48 + CTX-M15 + SHV-12 + TEM-1 + OXA-1 + DHA-1 1 32 >64 16 16 16 - TABLE 4
Bacterial susceptibility profile of NOSO-502 against colistin-resistant strains
Type of strain and gene mutation or gene conferring resistance (no. of isolates) MIC range (μg/ml) NOS CSTa Escherichia coli, colistin-resistant (25) mcr-1 (21) 1–4 4–16 mcr-2 (1) 1 8 mcr-3 (1) 1 16 Unknown (2) 1–2 16 Klebsiella pneumoniae, colistin resistant (46) pmrA G53S substitution (2) 1–2 32–128 pmrB T157P substitution (6) 0.25–16 8–32 pmrB L17Q substitution (1) 1 32 phoQ R16C substitution (1) 2 >128 mgrB full deletion (5) 0.5–1 16–>128 mgrB premature termination (6) 0.5–1 32–128 mgrB IS5 between +74 and +75 (4) 0.5–2 16–128 mgrB W20R substitution (1) 0.5 32 mgrB W47R substitution (1) 1 8 mgrB IS1R into promoter between −45 and −46 (3) 0.5–1 32–128 mgrB M27K substitution (1) 2 32 mgrB N42Y and K43I substitutions (1) 2 32 mgrB ISKpn14 into promoter between −28 and −29 (2) 0.5–2 64 mgrB IS903B between +69 and +70 (2) 0.25–1 64 mgrB IS1R between +44 and +45 (2) 1 128 mgrB ISKpn26-like between +74 and +75 (2) 1 128–>128 crrB P151L substitution (1) 128 >128 crrB G183V substitution (1) 64 >128 crrB F84S substitution (1) 8 128 crrB N141Y substitution (1) 16 >128 mcr-1 (1) 0.5 32 Unknown (1) 0.5 32 ↵a CST, colistin.
