Antimicrobial Activities of Ceragenins against Clinical Isolates of Resistant Staphylococcus aureus

Abstract

The rise in the rates of glycopeptide resistance among Staphylococcus aureus isolates is concerning and underscores the need for the development of novel potent compounds. Ceragenins CSA-8 and CSA-13, cationic steroid molecules that mimic endogenous antimicrobial peptides, have previously been demonstrated to possess broad-spectrum activities against multidrug-resistant bacteria. We examined the activities of CSA-8 and CSA-13 against clinical isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycinintermediate S. aureus (hVISA), as well as vancomycin-resistant S. aureus (VRSA) and compared them to those of daptomycin, linezolid, and vancomycin by susceptibility testing and killing curve analysis. We also examined CSA-13 for its concentration-dependent activity, inoculum effect, postantibiotic effect (PAE), and synergy in combination with various antimicrobials. Overall, the MICs and minimal bactericidal concentrations of CSA-13 were fourfold lower than those of CSA-8. Time-kill curve analysis of the VRSA, VISA, and hVISA clinical isolates demonstrated concentration-dependent bactericidal killing. An inoculum effect was also observed when a higher starting bacterial density was used, with the time required to achieve 99.9% killing reaching 1 h with a 6-log 10 -CFU/ml starting inoculum, whereas it was >24 h with a 8-to 9-log 10 -CFU/ml starting inoculum with 10؋ the MIC (P < 0.001). A concentration-dependent PAE was demonstrated with CSA-13, nearly doubling from 2؋ to 4؋ the MIC (P ‫؍‬ 0.03). With respect to the CSA-13 antimicrobial combinations, time-kill curve analysis showed no difference in the log 10 CFU/ml at 24 h for the majority of the organisms tested. However, early synergy at 4 to 8 h was detected against the VRSA Pennsylvania strain (2002) when CSA-13 was tested in combination with gentamicin, while early additivity was demonstrated against all of the other organisms.

Role of the HefC Efflux Pump inHelicobacter pyloriCholesterol-Dependent Resistance to Ceragenins and Bile Salts

“…This study is the first report to discover a ceragenin resistance mechanism, namely, that cholesterol confers resistance of H. pylori to ceragenins. Ceragenins are gaining momentum as novel cationic antimicrobial compounds related to bile salts that can kill antibiotic-resistant pathogens (8,9). Since these are easily synthesized in the laboratory yet are not peptides, studies can be conducted in vitro and in vivo.…”

“…Potency of the ceragenins varies from compound to compound, based on side groups added, solubility, and degree of charge (with greater positive charge correlating with greater antimicrobial activity). Importantly, ceragenins can kill bacterial pathogens that are resistant to multiple antibiotics, including methicillin-resistant Staphylococcus aureus (9) and multidrug-resistant Pseudomonas aeruginosa (8). They are also acid stable and water soluble.…”

Relationship of In Vitro Synergy and Treatment Outcome with Daptomycin plus Rifampin in Patients with Invasive Methicillin-Resistant Staphylococcus aureus Infections

“…The MIC and minimum biofilm eradication concentration (MBEC) were determined using a previously described transferable solid-phase pin-lid method (10). Synergy testing was evaluated by two methods: (i) checkerboard analysis with standard definitions of fractional inhibitory concentrations (FIC) (synergy, FIC Յ 0.5; indifference, FIC of Ͼ0.5 but Յ4; antagonism, FIC Ͼ 4) (11); (ii) 24-hour time-kill studies, with concentrations of daptomycin that are 0.5 to 4 times the organism MIC alone and concentrations of rifampin that are 0.5 times the MIC (synergy, Ն2 logs kill; additivity, 1 to 2 logs kill; indifference, 1 log kill to 1 log growth; antagonism, Ն1 log growth) (12). In this fashion, at least one of the antibiotics (rifampin) was present in a concentration with a minimal effect on growth when used alone in order to assess its interaction with daptomycin.…”

Core&ndash;shell magnetic nanoparticles display synergistic antibacterial effects against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> when combined with cathelicidin LL-37 or selected ceragenins

“…40 Ceragenins possess strong bactericidal activity against Gram-positive and Gram-negative bacteria, including MDR strains. [41][42][43][44][45][46] Significant membrane activity of CSAs results in bacterial membrane permeabilization and depolarization. 44,47 Previous studies indicate that antimicrobial activity of ceragenins against Gram-negative bacteria is usually lower than the effects against Gram-positive species.…”