Coordination Complexes to Combat Bacterial Infections: Recent Developments, Current Directions and Future Opportunities

Abstract

Drug discovery aimed at the efficient eradication of life‐threatening bacterial infections, especially in light of the emergence of multi‐drug resistance of pathogenic bacteria, has remained a challenge for medicinal chemists over the past several decades. As nutrient acquisition and metabolism at the host‐pathogen interface become better elucidated, new drug targets continue to emerge. Metal homeostasis is among these processes, and thus provides opportunities for medicinal inorganic chemists to alter or disrupt these processes selectively to impart bacteriostatic or bacteriotoxic effects. In this minireview, we showcase some of the recent work from the field of metal‐based antibacterial agents and highlight divergent strategies and mechanisms of action.

Effects of 4‐Br‐A23187 on Bacillus subtilis cells and unilamellar vesicles reveal it to be a potent copper ionophore

“…Especially, excess copper is known to displace metal ions such as iron from their protein binding sites, impairing protein function [7]. Since the maintenance of metal ion homeostasis is essential for growth and survival of bacteria, it is considered a promising target for antibiotic development [8].…”

“…Ionophores, which transport ions across biological membranes, offer another means to manipulate cellular ion composition to investigate physiological effects. Examples of commonly used ionophores include valinomycin, which transports potassium [8], or calcimycin (A23187) and ionomycin, which transports zinc, manganese, and calcium [11]. For most ionophores, transport properties were characterized in vitro in model systems comprising model membranes and a single ion species available for transport.…”

“…In vitro, 4-Br-A23187 has almost identical transport properties, except for a drastically reduced calcium transport rate (more than ten times lower than calcimycin) [11]. The bromination of 4-Br-A23187 destabilizes 2:1 ionophore/ion complexes and, while other ions can be transported in a 1:1 complex, calcium, due to its high coordination number (6)(7)(8), readily recruits a water molecule and ionophore-calcium-water complexes cannot pass the cellular membrane as easily [11,19]. While in vivo transport rates…”

Metal Complexes as Antifungals? – From a Crowd-Sourced Compound Library to First In Vivo Experiments

“…However, there have been only few systematic studies of anti-infective metal complexes until recently. [24][25][26][27] In the last few years, several research groups, including ours, have published a number of reports on the promising antibacterial properties of metal complexes. [28][29][30][31] We recently reported the first systematic study on the antimicrobial properties of >300,000 molecules, focusing on ~1000 metal-containing compounds in the dataset.…”

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

“…The emergence of bacteria with resistance to currently used antibiotics, combined with the paucity of new compounds in the pipeline necessitates the development of targeted novel antibiotics with new mechanisms of action. 5,6 Bacterial virulence is closely associated with nutrient acquisition, which is essential for bacterial growth and proliferation. 7 During an infection, iron -an indispensable micronutrient, essential for a plethora of cellular reactions in both humans and pathogens, is restricted for bacterial uptake as the available iron is tightly sequestered by host proteins such as -hemoglobin, transferrin and ferritin.…”