N-heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria.
In an effort to identify novel, broad-spectrum inhibitors against the metallo-β-lactamases (MβLs), several N-heterocyclic derivatives were tested as inhibitors of MβLs CcrA, ImiS, and L1, which are representative enzymes from the distinct MβL subclasses. Three N-heterocyclic dicarboxylic acid derivatives were competitive inhibitors of CcrA and L1, exhibiting K(i) values ≤2 μM, while only 2,4-thiazolidinedicarboxylic acid (1b) was a competitive inhibitor of ImiS. Two 2-mercapto-1,3,4-thiadiazole derivatives were noncompetitive inhibitors of CcrA and ImiS, exhibiting K(i) values <7 μM; however, these same compounds did not inhibit L1. Two 2-mercapto-1,3,4-triazole derivatives were shown not to inhibit any of the tested MβLs. The N-heterocyclic derivatives were tested for antibacterial activity by examining the MIC values for existing antibiotics in the presence/absence of these derivatives. Consistent with the steady-state inhibition data, the inclusion of three N-heterocyclic dicarboxylic acid derivatives resulted in lower MIC values when using Escherichia coli BL21(DE3) cells containing the CcrA or L1 plasmids or Klebsiella pneumoniae (ATCC 700603), while 1b was the only dicarboxylic acid derivative to lower the MIC value of E. coli cells containing the ImiS plasmid. Inclusion of the 2-mercapto-1,3,4-thiadiazole derivatives resulted in lower MIC values for E. coli cells containing ImiS or L1 plasmids; however, these derivatives did not alter the MIC values for K. pneumoniae or E. coli cells containing the L1 plasmid. None of the N-heterocyclic derivatives affected the MIC of two methicillin resistant Staphylococcus aureus (MRSA) strains. Taken together, these studies demonstrate that N-heterocyclic dicarboxylic acids 1a-c and pyridylmercaptothiadiazoles 2a,b are good scaffolds for future broad-spectrum inhibitors of the MβLs.
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069, PR China.
Lei
L
Feng
Ke-Wu
KW
Yang
Li-Sheng
LS
Zhou
Jian-Min
JM
Xiao
Xia
X
Yang
Le
L
Zhai
Yi-Lin
YL
Zhang
Michael W
MW
Crowder
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases