Preparation, Gram-Negative Antibacterial Activity, and Hydrolytic Stability of Novel Siderophore-Conjugated Monocarbam Diols (original) (raw)
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Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity
Journal of Medicinal Chemistry, 2013
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogs with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogs suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P.aeruginosa strain PAO1.
Siderophores as "Trojan Horses": tackling multidrug resistance?
Frontiers in microbiology, 2014
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug−target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptormediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
Antimicrobial Agents and Chemotherapy, 1992
We describe here the mechanism of inhibition of two new siderophore-beta-lactam conjugates against Escherichia coli X580. One conjugate is a spermidine-based catechol siderophore-carbacephalosporin (JAM-2-263), and the other is an N5-acetyl-N5-hydroxy-L-ornithine tripeptide hydroxamate siderophore-carbacephalosporin (EKD-3-88). In an agar diffusion test, both conjugates produced large inhibitory zones against strain X580. Resistant strains (i.e., JAMR and EKDR) could be isolated after exposure of X580 to the conjugates JAM-2-263 and EKD-3-88, respectively. No cross-resistance was observed in these individual isolates. JAMR and EKDR were studied further to elucidate the mechanism of inhibition of each conjugated drug. The affinities of JAM-2-263 and EKD-3-88 for penicillin-binding proteins (PBPs) of isolated inner membranes were determined by a competition assay with 125I-penicillin V. JAM-2-263 targeted primarily PBPs 1A/B and 5/6, while EKD-3-88 targeted PBPs 1A/B and 3. Strains X5...
Siderophore Receptor-Mediated Uptake of Lactivicin Analogues in Gram-Negative Bacteria
Journal of Medicinal Chemistry, 2014
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug−target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptormediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
Journal of medicinal chemistry, 2018
Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3) were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C and D β-lactamases with unprecedented k2/K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C β-lactamses rapidly, but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes via mass spectrometry. Crystallography revealed that the KPC-2-compounds 1-3 structures adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were efficiacous in murine peritonitis and neutropenic lung infection models using MDR Acinetobacte...
Activity of siderophores against drug-resistant Gram-positive and Gram-negative bacteria
Infection and Drug Resistance, 2018
Infections by drug-resistant bacteria are life-threatening. As iron is a vital element for the growth of bacteria, iron-chelating agents (siderophores) can be used to arrest their multiplication. Exogenous siderophores-exochelin-MS and deferoxamine-B-were evaluated for their inhibitory activity against methicillin-resistant Staphylococcus aureus and metallo-β-lactamase producers-Pseudomonas aeruginosa and Acinetobacter baumannii-by disc diffusion, microbroth dilution, and turbidimetric growth assays. The drug-resistant isolates were inhibited by the synergistic activity of siderophores and antibiotics. Minimum inhibitory concentration of exochelin-MS+ampicillin for different isolates was between 0.05 and 0.5 mg/mL. Minimum inhibitory concentration of deferoxamine-B+ampicillin was 1.0 mg/mL and greater. Iron-chelation therapy could provide a complementary approach to overcome drug resistance in pathogenic bacteria.
Prospects for the next anti-Pseudomonas drug
Current Opinion in Pharmacology, 2009
Pseudomonas aeruginosa is one of the most dreaded Gramnegative bacterial pathogens in hospitals. Not only it is among the most frequently isolated Gram-negative organisms in bloodstream and wound infections, pneumonia, intra-abdominal-sepsis and urogenital-sepsis, but also it is frequently found in patients with comorbid illnesses and compromised by in-dwelling catheters, tubes and surgery where mortality rates of more than 60% have been reported. Besides its intrinsic resistance to a number of widely used antibiotics, Pseudomonas also managed to acquire resistance via additional mechanisms, including target mutations, increased expression of efflux pumps and of antibiotic-degrading enzymes. Taken together, the increased incidence in certain types of infections, the increased use of invasive devices in the hospital as well as the increased frequency of multi-resistant Pseudomonas strains, have clearly led to a shortage of treatment options for nosocomial Pseudomonas infections. Even the recommended combination therapy of an antibiotic of the b-lactam class together with an aminoglycoside or a fluoroquinolone, is no longer always successful and sometimes a polymyxin has to be given as last resort. Despite growing concerns of clinicians and medical societies about the very limited number of novel drugs in the pipeline to fight multi-resistant Pseudomonas strains, only a very small number of novel anti-Pseudomonas drugs are currently in late stage of pre-clinical or clinical development. However, and possibly as a reflection of the magnitude of the problem, quite a variety of approaches are being pursued. Among these are next-generation analogues of successful antibiotic classes (e.g. novel b-lactams and combinations of novel b-lactamase inhibitors with known penicillins or cephalosporins), antibodies, phages and selective peptides. It is to be hoped that a number of these novel drugs will show clinical utility and reach the market over the next 6-10 years.
Pharmaceuticals, 2021
The siderophore–antibiotic conjugate LCB10-0200 (a.k.a. GT-1) has been developed to combat multidrug-resistant Gram-negative bacteria. In this study, the in vitro activity of LCB10-0200 and LCB10-0200/avibactam (AVI) has been investigated against carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Minimal inhibitory concentrations (MICs) of LCB10-0200, LCB10-0200/AVI, aztreonam, aztreonam/AVI, ceftazidime, ceftazidime/AVI, and meropenem were measured using the agar dilution method. Whole genome sequencing was performed using Illumina and the resistome was analyzed. LCB10-0200 displayed stronger activity than the comparator drugs in meropenem-resistant E. coli and K. pneumoniae, and the addition of AVI enhanced the LCB10-0200 activity to MIC ≤ 0.12 mg/L for 90.5% of isolates. In contrast, whereas LCB10-0200 alone showed potent activity against meropenem-resistant A. baumannii and P. aeruginosa at MIC ≤ 4 mg/L for 84.3% of...