Elucidating the effect of iron acquisition systems in Klebsiella pneumoniae on susceptibility to the novel siderophore-cephalosporin cefiderocol

Abstract

Background Cefiderocol (CFDC) is a novel siderophore-cephalosporin, effective against multidrug-resistant Gram-negative bacteria. As it has a siderophore side chain, it can utilize iron acquisition systems for penetration of the bacterial outer membrane. We aimed to elucidate the role of siderophores and iron uptake receptors in defining Klebsiella pneumoniae susceptibility to CFDC. Methods Initially, 103 K. pneumoniae strains were characterized for susceptibility to different antibiotics including CFDC. CFDC minimum inhibitory concentrations (MIC) were determined in iron-depleted and iron-enriched conditions. Iron uptake genes including siderophores, their receptors, ferric citrate (fecA) and iron uptake (kfu) receptors were detected by PCR in all the strains. For 10 selected strains, gene expression was tested in iron-depleted media with or without CFDC treatment and compared to expression in iron-enriched conditions. Results CFDC exhibited 96.1% susceptibility, being superior to all the other antibiotics (MIC50: 0.5 and MIC90: 4 μg/ml). Only three strains (2.9%) were intermediately susceptible and a pandrug resistant strain (0.97%) was resistant to CFDC (MIC: 8 and 256 μg/ml, respectively). The presence of kfu and fecA had a significant impact on CFDC MIC, especially when co-produced, and if coupled with yersiniabactin receptor (fyuA). CFDC MICs were negatively correlated with enterobactin receptor (fepA) expression and positively correlated with expression of kfu and fecA. Thus, fepA was associated with increased susceptibility to CFDC, while kfu and fecA were associated with reduced susceptibility to CFDC. CFDC MICs increased significantly in iron-enriched media, with reduced expression of siderophore receptors, hence, causing less drug uptake. Conclusion Iron acquisition systems have a significant impact on CFDC activity, and their altered expression is a factor leading to reduced susceptibility. Iron concentration is also a major player affecting CFDC susceptibility; therefore, it is essential to explore possible ways to improve the drug activity to facilitate its use to treat infections in iron-rich sites.

Virulence Characteristics and Molecular Typing of Carbapenem-Resistant ST15 Klebsiella pneumoniae Clinical Isolates, Possessing the K24 Capsular Type

“…The high rate of enterobactin expression (94.87%, Table 2 ) was consistent with previous studies [ 56 , 57 , 58 , 59 ] and further supported the pathogenic potential of the isolates. Furthermore, aerobactin was also reported to be an important determinant of virulence of K. pneumoniae [ 16 ] if present, although it was more rarely found in Klebsiella .…”

“…Its reported rates range from 3–6% [ 21 ], similar to our findings (5.12%). Although in our study no serious outcomes were registered among the patients infected by the isolates, evidence in the literature is mounting that K. pneumoniae strains carrying acquired siderophores have enhanced capacities to cause invasive diseases [ 17 , 59 , 60 , 61 , 62 ].…”

Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens

“…To further benchmark and contextualize the antibacterial activity of our triscatecholamide conjugates, we performed a comparative analysis of Cfdc, Ent-Amp, and TC-Amp activity against eight Gram-negative bacterial pathogens in the modified M9 medium (Table ). Under these conditions, Cfdc treatment afforded MIC values that were generally consistent with those previously reported for Pa, Ab, and Kp strains, , and ≥100-fold lower than the MIC values of Amp. Overall, the Ent- and TC-based SACs performed comparably to Cfdc.…”

Design and Synthesis of Novel Antimicrobial Agents

“…Bacteria produce siderophores, which are then released into the environment to chelate iron with an extremely high affinity [ 227 ]. In order to treat Enterobacteriaceae that are multidrug resistant (MDR) and carbapenem resistant (CR), including K. pneumoniae , cefiderocol (CFDC) ( 149 , Figure 15 ) binds to penicillin-binding proteins, inhibiting the formation of peptidoglycan and ultimately killing the bacteria [ 228 , 229 ]. Using the Gram-negative bacteria’s outer membrane-located iron transport mechanism or passive diffusion, CFDC binds to ferric iron (Fe 3+ ) and passes into the periplasmic region, where it detaches iron and enables the presentation of CFDC in large concentrations [ 230 , 231 ].…”

“…Using the Gram-negative bacteria’s outer membrane-located iron transport mechanism or passive diffusion, CFDC binds to ferric iron (Fe 3+ ) and passes into the periplasmic region, where it detaches iron and enables the presentation of CFDC in large concentrations [ 230 , 231 ]. In their study of the susceptibility of Klebsiella pneumoniae to CFDC under iron-depleted and iron-enriched environments, Daoud et al [ 229 ] discovered that CFDC had a susceptibility of 96.1%, which was higher than that of any other antibiotic. The findings also demonstrated that CFDC MICs increased in iron-enriched media where iron uptake receptors ( fecA and/or kfu ) are expressed, resulting in a loss of drug activity.…”