Ceragenins (CSAs) that mimic the activities of antimicrobial peptides may be new options for the treatment of infections caused by multidrug-resistant pathogens. This study investigated the antibacterial activities of eight different ceragenins against MDR pathogens and the synergistic effects of some ceragenins in combinations with antibiotics (meropenem-MEM, ceftazidime + avibactam-CZA, tigecycline-TIG). A disc diffusion method was used for antibiotic susceptibility tests, a broth microdilution, and checkerboard methods were used to detect minimum inhibitory concentrations (MICs) and the effects of combinations, respectively. While MIC₉₀ values CSA-13, CSA-44, CSA-131 against Klebsiella pneumoniae isolates had similar effect with MEM (8 µg/ml); CSA-13, CSA-44, CSA-131, CSA-138, and CSA-144 had better activity than MEM against Acinetobacter baumannii and Pseudomonas aeruginosa isolates. In particular, CSA-44 and CSA-131 were effective against A. baumannii and P. aeruginosa isolates which resistant to both COL and MEM. CSA-44+MEM and CSA-131+CZA combinations showed synergistic activity against most (70%) of MDR- E. coli isolates. Although TIG is known to have weak activity in nonfermentative bacteria, CSA-44+TIG combination showed synergistic activity against two (17%) of the A. baumanni isolates. In addition, CSA-44+TIG and CSA-131+TIG combinations showed additive effects against all P. aeruginosa isolates. Antagonism was not detected in any of the combinations. CSA-44 and CSA-131 alone/or in combinations with MEM or CZA can be considered as new alternative treatments in serious infections caused by MDR pathogens.

2023-08-17·Microbiology spectrum

Glyoxylate Shunt and Pyruvate-to-Acetoin Shift Are Specific Stress Responses Induced by Colistin and Ceragenin CSA-13 in Enterobacter hormaechei ST89.

Article

作者: Fiedoruk, Krzysztof ; Zakrzewska, Magdalena ; Bucki, Robert ; Savage, Paul B ; Prasad, Suhanya V

Ceragenins, including CSA-13, are cationic antimicrobials that target the bacterial cell envelope differently than colistin. However, the molecular basis of their action is not fully understood. Here, we examined the genomic and transcriptome responses by Enterobacter hormaechei after prolonged exposure to either CSA-13 or colistin. Resistance of the E. hormaechei 4236 strain (sequence type 89 [ST89]) to colistin and CSA-13 was induced in vitro during serial passages with sublethal doses of tested agents. The genomic and metabolic profiles of the tested isolates were characterized using a combination of whole-genome sequencing (WGS) and transcriptome sequencing (RNA-seq), followed by metabolic mapping of differentially expressed genes using Pathway Tools software. The exposure of E. hormaechei to colistin resulted in the deletion of the mgrB gene, whereas CSA-13 disrupted the genes encoding an outer membrane protein C and transcriptional regulator SmvR. Both compounds upregulated several colistin-resistant genes, such as the arnABCDEF operon and pagE, including genes coding for DedA proteins. The latter proteins, along with beta-barrel protein YfaZ and VirK/YbjX family proteins, were the top overexpressed cell envelope proteins. Furthermore, the l-arginine biosynthesis pathway and putrescine-ornithine antiporter PotE were downregulated in both transcriptomes. In contrast, the expression of two pyruvate transporters (YhjX and YjiY) and genes involved in pyruvate metabolism, as well as genes involved in generating proton motive force (PMF), was antimicrobial specific. Despite the similarity of the cell envelope transcriptomes, distinctly remodeled carbon metabolism (i.e., toward fermentation of pyruvate to acetoin [colistin] and to the glyoxylate pathway [CSA-13]) distinguished both antimicrobials, which possibly reflects the intensity of the stress exerted by both agents. IMPORTANCE Colistin and ceragenins, like CSA-13, are cationic antimicrobials that disrupt the bacterial cell envelope through different mechanisms. Here, we examined the genomic and transcriptome changes in Enterobacter hormaechei ST89, an emerging hospital pathogen, after prolonged exposure to these agents to identify potential resistance mechanisms. Interestingly, we observed downregulation of genes associated with acid stress response as well as distinct dysregulation of genes involved in carbon metabolism, resulting in a switch from pyruvate fermentation to acetoin (colistin) and the glyoxylate pathway (CSA-13). Therefore, we hypothesize that repression of the acid stress response, which alkalinizes cytoplasmic pH and, in turn, suppresses resistance to cationic antimicrobials, could be interpreted as an adaptation that prevents alkalinization of cytoplasmic pH in emergencies induced by colistin and CSA-13. Consequently, this alteration critical for cell physiology must be compensated via remodeling carbon and/or amino acid metabolism to limit acidic by-product production.

2022-07-01·The Journal of Antibiotics

In vitro activity of ceragenins against Burkholderia cepacia complex

Article

作者: Savage, Paul B ; Bozkurt-Guzel, Cagla ; Demir, Elif Sena ; Oyardi, Ozlem ; Altay, Havva Ozlem

Burkholderia cepacia complex (Bcc) species are aerobic, Gram-negative and non-fermantative bacilli. Bcc can cause clinical symptoms in patients with cystic fibrosis, ranging from asymptomatic carriage to fatal pneumonia. A pressing need exists for new antimicrobial agents that target Bcc. Ceragenins, CSA-13, CSA-131 and CSA-131 with 5% Pluronic® F127 (CSA-131P), were evaluated against Bcc clinical isolates (n = 42). MICs of ceragenins and conventional antibiotics were determined. Time-kill curve experiments were performed with 1x, 4x MICs of ceragenins and sulfamethoxazole-trimethoprim (SXT), levofloxacin. MIC₅₀/ MIC₉₀ results (mg l^-1) of CSA-13, CSA-131 and CSA-131P were determined as 16/64, 16/128 and 16/128, respectively. CSA-13 and CSA-131 showed bactericidal activity. CSA-13 - levofloxacin combination displayed synergistic activity against Bcc. First-generation (CSA-13) and second-generation (CSA-131 and CSA-131P) ceragenins have significant antimicrobial effects on Bcc. The findings of this study demonstrate that combinations of ceragenins with currently marketed antibiotics could be synergistic in vitro against Bcc isolates. These results suggest that combination therapy with conventional antibiotics could be an alternative approach for treating Bcc infections in the future.

100 项与 CSA-13 相关的药物交易

登录后查看更多信息