meropenem and Hemolysis

The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 μg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.

Topics: Alkylation; Anti-Bacterial Agents; Bacteria; Biofilms; Cell Membrane Permeability; Chemistry Techniques, Synthetic; Drug Resistance, Multiple; Drug Stability; Hemolysis; Humans; Hydrophobic and Hydrophilic Interactions; Peptidomimetics

The activity of β-lactam antibiotics is compromised by metallo-β-lactamases (MBLs). Herein, a series of dithiocarbamate derivatives were designed and synthesized. Their antibacterial activities were tested in combination with meropenem (MEM) against several MBL (NDM and IMP type)-producing clinical isolates. Clinical isolates harboring NDM-1 and IMP-4 became susceptible to MEM when it was combined with dithiocarbamate compounds 4a, 4b or 4f synthesized in this work. Compounds 4a and 4b increased the effectiveness of MEM by up to 2560 times against strains. In vitro bactericidal dynamics tests showed that bacteria died within 24 h when they were treated with compound 4f + MEM. Compounds 4a, 4b and 4f were non-hemolytic and exhibited low toxicity toward HeLa cells in vitro. These data show that compounds containing dithiocarbamate functional group may be helpful in the development of MBL inhibitors.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Enterobacteriaceae; Erythrocytes; HeLa Cells; Hemolysis; Humans; Meropenem; Microbial Sensitivity Tests; Thiocarbamates; Zinc

Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics. Combination studies indicate the ability of these conjugates to synergize rifampicin and minocycline against MDR and extensively drug resistant (XDR) P. aeruginosa isolates and enhance efficacy of both antibiotics in the Galleria mellonella larvae in vivo infection model. Mode of action studies indicate that the amphiphilic tobramycin-lysine adjuvants enhance outer membrane cell penetration and affect the proton motive force, which energizes efflux pumps. Overall, this study provides a strategy for generating effective antibiotic adjuvants that overcome resistance of rifampicin and minocycline in MDR and XDR Gram-negative bacteria including P. aeruginosa.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Hemolysis; Lysine; Microbial Sensitivity Tests; Minocycline; Models, Biological; Rifampin; Tobramycin

Recent efforts toward combating antibiotic resistance in bacteria have focused on Gram-positive bacteria; however, multidrug-resistant Gram-negative bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compounds that enhance the susceptibility of drug-resistant strains of bacteria to currently approved antibiotics. This paper describes the synthesis and biological activity of a library of aryl amide 2-aminoimidazoles based on a lead structure from an initial screen. A small molecule was identified from this library that is capable of lowering the minimum inhibitory concentration of β-lactam antibiotics by up to 64-fold.

Topics: Animals; beta-Lactam Resistance; Cell Line; Cell Survival; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Hemolysis; Humans; Keratinocytes; Microbial Sensitivity Tests; Sheep; Small Molecule Libraries

We present the first reported case of severe intravascular haemolysis associated with the use of meropenem in a 64 year old man. The report highlights a further possible drug related cause of intravascular haemolysis. The patient, who had a background of dialysis dependent renal failure, epilepsy and learning difficulties, was admitted to the intensive care unit following laparotomy and large bowel resection. His background also included a reported childhood allergy to penicillin. Along with initial haemodynamic and ventilatory support he was treated with cefuroxime, metronidazole and gentamicin without incident. He went on to develop an abdominal collection, for which treatment included meropenem. Associated with the administration of meropenem was the development of severe intravascular haemolysis confirmed by laboratory analysis and microscopy, which resolved on cessation of meropenem therapy. We discuss the possible mechanisms involved in the development of drug induced haemolysis and suggest the most likely cause in this case.

Topics: Acute Disease; Anti-Bacterial Agents; Gram-Negative Bacterial Infections; Hemolysis; Humans; Male; Meropenem; Middle Aged; Severity of Illness Index; Thienamycins