<p>NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131</p>

Abstract

Background and Purpose: Treatment of infections caused by NDM-1 carbapenemaseproducing Enterobacteriaceae (CPE) represents one of the major challenges of modern medicine. In order to address this issue, we tested ceragenins (CSAs-cationic steroid antimicrobials) as promising agents to eradicate various NDM-1-producing Gram-negative enteric rods. Materials and Methods: Susceptibility to CSA-13, CSA-44, and CSA-131 of four reference NDM-1 carbapenemase-producing strains, ie, Escherichia coli BAA-2471, Enterobacter cloacae BAA-2468, Klebsiella pneumoniae subsp. pneumoniae BAA-2472, and K. pneumoniae BAA-2473 was assessed by MIC/MBC testing of planktonic cells as well as biofilm formation/disruption assays. To define the mechanism of CSAs bactericidal activity, their ability to induce generation of reactive oxygen species (ROS), permeabilization of the inner and outer membranes, and their mechanical and adhesive properties upon CSA addition were examined. Additionally, hemolytic assays were performed to assess CSAs hemocompatibility. Results: All tested CSAs exert substantial bactericidal activity against NDM-1-producing bacteria. Moreover, CSAs significantly prevent biofilm formation as well as reduce the mass of developed biofilms. The mechanism of CSA action comprises both increased permeability of the outer and inner membrane, which is associated with an extensive ROS generation. Additionally, atomic force microscopy (AFM) analysis has shown morphological alterations in bacterial cells and the reduction of stiffness and adhesion properties. Importantly, CSAs are characterized by low hemolytic activity at concentrations that are bactericidal. Conclusion: Development of ceragenins should be viewed as one of the valid strategies to provide new treatment options against infections associated with CPE. The studies presented herein demonstrate that NDM-1-positive bacteria are more susceptible to ceragenins than to conventional antibiotics. In effect, CSA-13, CSA-44, and CSA-131 may be favorable for prevention and decrease of global burden of CPE.

Physics Comes to the Aid of Medicine—Clinically-Relevant Microorganisms through the Eyes of Atomic Force Microscope

“…Moreover, considerable changes of mechanical properties of the tested bacteria were noted accompanied by a decrease of cellular stiffness and adhesion force. Overall, all of these results obtained on the nano-level extend our knowledge on the utility of ceragenins in the treatment of drug-resistant bacterial pathogens [71].…”

“…Likewise, in our research ( Figure 3 ), we used AFM to assess the bactericidal effects of ceragenins (CSA), i.e., synthetic, lipid-based analogs of natural antimicrobial peptides, against NDM-1 carbapenemase-producing K. pneumoniae [ 71 ]. In a compelling number of studies, ceragenins were demonstrated as potent antimicrobial agents with a membrane-permeabilizing mechanism of action [ 2 , 5 , 72 ].…”

Bactericidal Properties of Rod-, Peanut-, and Star-Shaped Gold Nanoparticles Coated with Ceragenin CSA-131 against Multidrug-Resistant Bacterial Strains

“…On the other hand, to address the possible toxicity of CSAs used alone, our previous data underlined that CSA-131 at concentrations ranging from 1–10 µg/mL caused no significant hemolysis, even after 12 h of incubation [ 35 ]. Moreover, the recent data also demonstrated that MNP-CSA-13 at concentrations of 1–100 µg/mL had no effect on the hemoglobin released from RBC [ 59 ].…”

“…Whereas the remaining members belong to the second generation of CSAs [ 34 ]. A variety of studies confirmed that the second-generation of CSAs, notably CSA-131, possess potent antimicrobial activity against a broad spectrum of microorganisms such as carbapenem-resistant E. coli, K. pneumoniae, E. cloacae [ 35 ], or P. aeruginosa [ 36 ]; colistin-resistant K. pneumoniae and Acinetobacter baumannii [ 37 , 38 ]; as well as uropathogenic E. coli strains [ 39 ]. Moreover, Hacioglu et al have demonstrated the antibiofilm activity of CSA-131 against C. albicans cells in both mono- and multispecies biofilms, i.e., comprising of C. albicans and MRSA or MSSA (methicillin-susceptible S. aureus ) strains [ 34 ].…”

“…It should be highlighted that our previous studies revealed noticeable antibacterial effects of CSA-131 against MDR strains [ 35 ]. However, it has not been studied whether Au NPs, functionalized by CSA-131, have potent antimicrobial activity suitable for more efficient treatment of infections.…”