Metal-based compounds against emerging infectious diseases

Abstract

Recent years, the outbreaks of emerging infectious diseases have been increased frequently, imposed unparalleled challenges on global public health. For example, COVID-19 pandemic spread rapidly and globally, causing widespread health crises. Meanwhile, antimicrobial resistance (AMR), the “silent epidemic” is also severe. It not only increases the difficulty of treating infections but also may trigger serious complications. Metal compounds have long been associated with infectious diseases. In this thesis, metal-based compounds were developed which may offer substantial potential for effective solutions for emerging infectious diseases.

In Chapter 2, a metal-tagged antibody approach was established to validate SARS-CoV-2 nsp13 (i.e. helicase) as a target of bismuth-based antivirals in virus-infected mammalian cells firstly. A series of bismuth-based compounds were then synthesized and screened. Certain bismuth compounds exhibit potency with Bi(Tro-NH2)3 to be the best (with an IC50 of 30 nM for ATPase activity). Bi(Ⅲ) compounds were found to suppress enzyme activities by interfering with the binding of ATP and DNA/RNA substrate to nsp13. Binding of Bi(III) compounds to nsp13 further disrupted the interaction between nsp12 (RNA polymerase) and nsp13 in infected mammalian cells. This work underlined the significance of helicase in the pursuit of more potent antiviral drugs to counteract SARS-CoV-2 infection. COVID-19 pandemic has also aroused attention to investigate the antiviral potential of Au(I) compounds.

Subsequently, in Chapter 3, nsp13 was used as a target to screen a panel of Au(I)-based compounds and found they could effectively inhibit both ATPase and DNA unwinding activities. Mechanistic studies revealed that Au(I) can not only displace the critical Zn(II) ions from nsp13, but also perturbate the DNA/RNA unwinding of nsp13 by disrupting the ATP binding. These findings added to our understanding of nsp13 as a potential target in metal-based drug development.

In Chapter 4, attention was paid to anti-microbial resistance (AMR). Bismuth based drugs in combination with different classes of antibiotics were found to eliminate multidrug-resistant P. aeruginosa without development of antibiotic resistance. Bi(Ⅲ) drugs were discovered to inhibit the electron transport chain and impaired efflux pump activity to facilitate antibiotic accumulation inside bacteria. The combination therapy showed potent antibacterial efficacy and low toxicity and enhanced the mice survival rate in vivo mouse lung-infection models. The findings demonstrated the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics, offering a new arsenal for AMR.

In Chapter 5, enhanced systemic absorption of bismuth (III) was sought. Complexes of Bi(III) with thiol-containing compounds (e.g. N-acetyl cysteine, Bi(NAC)3) showed potent synergistic effect with multiple antibiotics. Importantly, the survival rate can also be enhanced by oral administration. A biotin-based bismuth(III) probe was designed and synthesized, and 20 Bi(III)-binding proteins were identified, laying the foundation for mechanism of action of Bi(III) in restoring the activity of antibiotics.

Taken together, metal-based drug development has potential to play significant roles in combating emerging infectious diseases. With further understanding of mechanism of action and optimization of these lead compounds, metal-based drugs could become an essential component in safeguarding global health from emerging infectious threats.