Trojan Horse Antibiotics–A Novel Way to Circumvent Gram-Negative Bacterial Resistance?

Abstract

Antibiotic resistance has been emerged as a major global health problem. In particular, gram-negative species pose a significant clinical challenge as bacteria develop or acquire more resistance mechanisms. Often, these bacteria possess multiple resistance mechanisms, thus nullifying most of the major classes of drugs. Novel approaches to this issue are urgently required. However, the challenges of developing new agents are immense. Introducing novel agents is fraught with hurdles, thus adapting known antibiotic classes by altering their chemical structure could be a way forward. A chemical addition to existing antibiotics known as a siderophore could be a solution to the gram-negative resistance issue. Siderophore molecules rely on the bacterial innate need for iron ions and thus can utilize a Trojan Horse approach to gain access to the bacterial cell. The current approaches to using this potential method are reviewed.

Cefiderocol, a Siderophore Cephalosporin for Gram‐Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment

“…11 This concept of carrying compounds into other cells such as bacteria has been likened to the "Trojan horse." 12 Cefiderocol exposure increased in subjects with moderate and severe renal impairment and ESRD compared to those with normal renal function. Therefore, dose adjustments based on renal function would be needed so that the dose regimens will provide drug exposures comparable to that in subjects with normal renal function.…”

“…The catechol moiety of cefiderocol contributes to its potent antimicrobial activity against Gram‐negative bacteria including those resistant to other antibiotics by functioning as a siderophore, an iron‐complexing protein, to form a chelating complex with ferric iron and utilize the bacterial iron transport system to penetrate the outer membrane of the Gram‐negative organisms . This concept of carrying compounds into other cells such as bacteria has been likened to the “Trojan horse.”…”

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

“…Cefiderocol is a cephalosporin molecule with an attached catechol moiety on the 3-position side chain which binds to ferric iron [11]. Once across the outer membrane, the iron dissociates and the cephalosporin binds to penicillin-binding proteins (PBP), mainly PBP3, as other cephalosporins do to disrupt cell wall synthesis [11,13], contributing to a potent antimicrobial activity against Gram-negative bacteria. In addition, this antimicrobial activity of cefiderocol is enhanced by the high stability of cefiderocol to hydrolysis by nearly all β-lactamases, including both the serine and metallo-carbapenemases [14].…”

Metabolism, Excretion, and Pharmacokinetics of [14C]‐Cefiderocol (S‐649266), a Siderophore Cephalosporin, in Healthy Subjects Following Intravenous Administration

“…Blood samples for determination of total radioactivity cefiderocol equivalent concentrations in plasma and whole blood and for cefiderocol concentrations in plasma were collected before dosing and at 0.5, 1 (just before the end of infusion), 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after initiation of the infusion, and thereafter every 24 hours until discharge criteria were met. Blood samples for metabolic profiling in plasma were collected before dosing and at 1,2,4,8,12,16,24,48,72, and 96 hours after initiation of the infusion. Blood samples for determination of hematocrit values were collected at 1, 4, 16, 24, and 72 hours after initiation of the infusion.…”

“…Sample Preparation for Metabolite Profiling The total radioactivity in the plasma samples was not detected 24 hours after dosing, so the composite plasma samples from each subject were pooled across time points (1,2,4,8,12, and 16 hours after dosing) using the pooling method 17 for area under the concentration-time curve (AUC) calculation. Each pooled plasma sample (1 mL each) was extracted twice by 4 mL of trifluoroacetic acid/methanol (0.2:100, v/v) and centrifuged.…”