Bacterial virulence is closely associated with nutrient acquisition, which is essential for growth and proliferation of pathogens. Metal ions constitute essential nutrients, and the regulation of bacterial metal ion homeostasis within the host environment plays a pivotal role; however, unbound essential metal ions exhibit low bioavailability. Bacteria rely on targeting the hosts’ labile iron reserves through synthesis of endogenous, hydrophilic metallophores that are internalized using ATP-dependent bacterial transmembrane shuttles. These metallophores also retain affinity for non-essential xenometal ions with identical charge, comparable ionic radius and chemical hardness to the essential metal ion such as Ga3+ (0.76 Å), and can capitalize on siderophore-mediated active transport to the bacterial peri- and cytoplasm. Recent strategies to utilize these bacterial metal homeostasis pathways to deliver therapeutics has resulted in renewed interest in xenometals as alternative antibiotics. Specifically, our lab has demonstrated that the combination of Ga3+ with siderophore-antibiotic conjugates can produce a synergistic, growth inhibitory effect. Additionally, the use of short-lived isotopes of Ga3+, such as Ga-67 (suitable for single photon emission computed tomography/SPECT, t1/2 = 78h) or Ga-68 (sutiable for positron emission tomography/PET, t1/2 = 1.1h) provides means to efficiently study the pharmacokinetics of these novel pharmacophores in vivo. Herein, we will discuss our efforts in the design, synthesis, in vitro and in vivo assessment Ga3+-complexed siderophore-drug conjugates inspired by the natural product albomycin. While our first-generation construct Ga-D2 demonstrated broad-spectrum potency, the structural modification to incorporate an enzymatically cleavable linker moiety produced Ga-D5. Ga-D5 is exceptionally active against S.aureus strains with a MIC99 of 93 nM, comparing favorably to the parent antibiotic ciprofloxacin with an MIC98 of 1 µM. In vivo studies with 67Ga-D5 reveal a favorable, renal clearance profile with enhanced uptake in infected muscle tissue when compared to the control muscle. In vivo treatment studies are ongoing to demonstrate the efficacy of Ga-D5 as an IV-antibiotic treatment. Our work demonstrates that xenometal-based antibiotics can efficiently utilize the bacterial iron scavenging machinery to deliver and synergize with antibiotics with cytoplasmic targets.

A medicinal inorganic chemistry approach to devise antibiotics with enhanced efficacy

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.