Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Cefiderocol, and Novel Darobactin Analogs against Multidrug-Resistant Pseudomonas aeruginosa Isolates from Pediatric and Adolescent Cystic Fibrosis Patients

Abstract

Antimicrobial resistance (AMR) represents an ever increasing threat to the health care system. Even recently licensed drugs are often not efficient for the treatment of infections caused by Gram-negative bacteria, like Pseudomonas aeruginosa , a causative agent of lung infections. To address this unmet medical need, innovative antibiotics, which possess a new mode of action, need to be developed. Here, the antibiogram of clinical isolates derived from cystic fibrosis patients was generated and new bicyclic heptapeptides, which inhibit the outer membrane protein BamA, exhibited strong activity, also against multidrug-resistant isolates.

Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: a systematic review and meta-analysis

“…In about half of the cases (n=44, 51%), the studies lacked a clear definition or citation of the method for interpreting trailing (broth microdilution) or colonies within zone (disk diffusion). There were 14 data sets for which a method other than broth microdilution was used (n=9 disk diffusion [8,36,37,51,65,72,75,88,92,95], n=5 gradient strip [36,68,69,94,97]). Apotransferrin for medium preparation was reported on 4 data sets (2 studies [60,61]).…”

Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

“…infections, limiting the treatment options of Cefiderocol [ 116 ]. Different studies are ongoing to explore the efficacy of possible combinations with other antimicrobials [ 117 , 118 ].…”

New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development

“…baumannii), or Klebsiella pneumoniae (K. pneumoniae), against which many other antibiotics are not effective anymore. ,,,, Two derivatization series of darobactins published by Groß et al and Seyfert et al have confirmed the efficacy of scaffold modification by biotechnological engineering of the fully synthetic darobactin biosynthetic gene cluster (BGC) to enhance the bioactivity of analogues, , which was partly confirmed by the study of Marner et al The feasibility of modifications at specific positions of the core peptide was a prerequisite for analyzing their influence on antibacterial activity and for understanding how analogues of this novel compound class interact with its unique target BamA. These new insights together with the first described cocrystal structure of darobactin A ( DA ) and BamA helped establishing the structure–activity relationships of the different derivatives. , The earlier derivatization series increased the antibacterial activity of darobactins up to 128-fold for darobactin 22 ( D22 ) compared to native DA , even against clinical isolates of carbapenem-resistant A.…”

“…Consequently, the risk of cross-resistance is lower, and they are proven to exhibit an auspicious broad-spectrum Gram-negative activity against clinically relevant and multiresistant pathogens such as Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii), or Klebsiella pneumoniae (K. pneumoniae), against which many other antibiotics are not effective anymore. 11,12,15,19,20 Two derivatization series of darobactins published by Groß et al and Seyfert et al have confirmed the efficacy of scaffold modification by biotechnological engineering of the fully synthetic darobactin biosynthetic gene cluster (BGC) to enhance the bioactivity of analogues, 12,15 which was partly confirmed by the study of Marner et al 21 The feasibility of modifications at specific positions of the core peptide was a prerequisite for analyzing their influence on antibacterial activity and for understanding how analogues of this novel compound class interact with its unique target BamA. These new insights together with the first described cocrystal structure of darobactin A (DA) and BamA helped establishing the structure−activity relationships of the different derivatives.…”

“…baumannii (CRAB) and multidrug-resistant P. aeruginosa. ,, However, some positions, especially position 2 (Figure ), have not yet been subject to detailed investigation. Additional efforts to engineer antibacterial darobactin derivatives as potential future drugs are therefore a promising approach to fight the antibiotic crisis …”