Enteric Gram-negative bacteria, including Escherichia coli, biosynthesize and deploy the triscatecholate siderophore enterobactin (Ent) in the vertebrate host to acquire iron, an essential nutrient. We report that Ent-Cipro, a synthetic siderophore-antibiotic conjugate based on the native Ent platform that harbors an alkyl linker at one of the catechols with a ciprofloxacin cargo attached, affords targeted antibacterial activity against E. coli strains that express the pathogen-associated iroA gene cluster. Attachment of the siderophore to ciprofloxacin, a DNA gyrase inhibitor and broad-spectrum antibiotic that is used to treat infections caused by E. coli, generates an inactive prodrug and guides the antibiotic into the cytoplasm of bacteria that express the Ent uptake machinery (FepABCDG). Intracellular hydrolysis of the siderophore restores the activity of the antibiotic. Remarkably, Fes, the cytoplasmic Ent hydrolase expressed by all E. coli, does not contribute to Ent-Cipro activation. Instead, this processing step requires IroD, a cytoplasmic hydrolase that is expressed only by E. coli that harbor the iroA gene cluster and are predominantly pathogenic. In the uropathogenic E. coli UTI89 and CFT073, Ent-Cipro provides antibacterial activity comparable to unmodified ciprofloxacin. This work highlights the potential of leveraging and targeting pathogen-associated microbial enzymes in narrow-spectrum antibacterial approaches. Moreover, because E. coli include harmless gut commensals as well as resident microbes that can contribute to disease, Ent-Cipro may provide a valuable chemical tool for strain-selective modulation of the microbiota.
Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects. The enzyme is also reported to cause resistance against antitumor agents, such as cisplatin. Here we report the first covalently linked conjugates of cisplatin and COX inhibitors, which allow concerted transport of both drugs into tumor cells and simultaneous action on intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared to cisplatin and are even able to overcome cisplatin-related resistance of tumor cells. Furthermore, the conjugates provide tools for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents.
Carbaboranes are increasingly studied as pharmacophores, particularly as replacements for aromatic systems. However, especially ortho-carbaborane is prone to degradation of the cluster, which hampers biological application. This study demonstrates that deboronation of the cluster may not only lead to a more active analogue but can also improve the solubility and stability of a carbaborane-containing inhibitor. Notably, introduction of a nido-dicarbaborate cluster into the cyclooxygenase (COX) inhibitor indomethacin results in a remarkably increased inhibitory potency and selectivity for COX-2 relative to the respective phenyl analogue. The first crystal structure of a carbaborane-containing inhibitor bound to COX-2 further reveals a novel binding mode for the inhibitor that is strikingly different from that of indomethacin. These results indicate that nido-dicarbaborate is a promising pharmacophore exhibiting properties which are also highly beneficial for its introduction into other inhibitor classes.
Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells.
Bacterial iron uptake machinery can be hijacked for the targeted delivery of antibiotics into pathogens by attaching antibiotics to siderophores, iron chelators that are employed by bacteria to obtain this essential nutrient. We synthesized and evaluated Ent-SS-Cipro, a siderophore-antibiotic conjugate comprised of the triscatecholate siderophore enterobactin and the fluoroquinolone antibiotic ciprofloxacin that contains a self-immolative disulfide linker. This linker is designed to be cleaved after uptake into the reducing environment of the bacterial cytoplasm. We show that the disulfide bond of Ent-SS-Cipro is cleaved by reducing agents, including the cellular reductant glutathione, which results in release of the unmodified fluoroquinolone antibiotic. Antibacterial activity assays against a panel of Escherichia coli show that Ent-SS-Cipro exhibits activity against some, but not all, E. coli. This work informs the design of siderophore-antibiotic conjugates, particularly those carrying antibiotics with cytoplasmic targets that require release after uptake into bacterial cells, and indicates that disulfide linkers may not be generally applicable for conjugation strategies of antibiotics.
A tug-of-war between the mammalian host and bacterial pathogen for nutrients, including first-row transition metals (e.g. Mn, Fe, Zn), occurs during infection. Here we present recent advances about three metal-chelating metabolites that bacterial pathogens deploy when invading the host: staphylopine, staphyloferrin B, and enterobactin. These highlights provide new insights into the mechanisms of bacterial metal acquisition and regulation, as well as the contributions of host-defense proteins during the human innate immune response. The studies also underscore that the chemical composition of the microenvironment at an infection site can influence bacterial pathogenesis and the innate immune system.
Transition metals are essential nutrients for all organisms and important players in the hostmicrobe interaction. During bacterial infection, a tug-of-war between the host and microbe for nutrient metals occurs: the host innate immune system responds to the pathogen by reducing metal availability and the pathogen tries to outmaneuver this response. The outcome of this competition, which involves metal-sequestering host-defense proteins and microbial metal acquisition machinery, is an important variable for whether infection occurs. One strategy bacterial pathogens employ to overcome metal restriction involves hijacking abundant host metalloproteins. The obligate human pathogens Neisseria spp. express TonB-dependent transport systems that capture human metalloproteins, extract the bound metal ions, and deliver these nutrients into the bacterial cell. This Essay highlights structural and mechanistic investigations that provide insights into how Neisseria acquire iron from the Fe(III)-transport protein transferrin, the Fe(III)-chelating hostdefense protein lactoferrin, and the oxygen-transport protein hemoglobin, and obtain zinc from the metal-sequestering antimicrobial protein calprotectin.
Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase-2 (COX-2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource-intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data. The inclusion of full receptor and ligand flexibility into the molecular modeling of carborane-containing drug molecules may yield more definitive results, but is currently hindered by the lack of appropriate carborane force field parameters.
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