SUMMARY Multidrug-resistant (MDR) bacterial infections continue to outpace therapeutic innovation, undermining the efficacy of conventional antibiotics and exposing the limitations of the current drug pipeline. In this review, we critically examine the translational viability of peptide-based antimicrobials and siderophore conjugates—two classes of therapeutics often promoted as next-generation solutions against MDR pathogens. Rather than reiterating their mechanistic promise, we dissect the structural assumptions that underpin their design and expose the clinical blind spots that have hindered their success. While peptides offer membrane disruption, intracellular targeting, and, in some cases, selective bacterial killing, their efficacy remains context-dependent and is frequently compromised by host-driven proteolysis, poor bioavailability, and limited tissue penetration. Similarly, siderophore-based conjugates exploit iron uptake systems for targeted delivery, yet depend on bacterial receptors that are variably expressed, easily suppressed, or genetically lost during infection. The failure of cefiderocol in specific clinical settings exemplifies the vulnerability of “Trojan horse” approaches to metabolic plasticity and ecological interference. This review highlights the need for a paradigm shift—from broad biochemical optimism to receptor-aware, pathogen-stratified, and pharmacologically grounded strategies. Reframing these modalities within their biological and clinical constraints offers a more realistic foundation for the development of actionable peptide- and siderophore-based therapies against resistant bacterial infections.
Roque-Borda et al. (Wed,) studied this question.