Design, Synthesis and in Vivo Evaluation of 3-Arylcoumarin Derivatives of rhenium(I) Tricarbonyl Complexes as Potent Antibacterial Agents Against Methicillin-Resistant Staphylococcus Aureus (MRSA)

Abstract

<p>Preparation of a series of ten 3-arylcoumarin molecules, their respective <i>fac</i>-[Re(CO)<sub>3</sub>(bpy)L]<sup>+</sup> and <i>fac</i>-[Re(CO)<sub>3</sub>(L⁀L)Br] complexes. All compounds were tested for their antimicrobial efficacy. Whereas the 3-arylcoumarin ligands are virtually inactive against the human-associated pathogens with minimum inhibitory concentrations (MICs) > 150 µM, when coordinated to the <i>fac</i>-[Re(CO)<sub>3</sub>]<sup>+ </sup>core, most of the resulting complexes showed remarkable antibacterial potency<i>. </i>Several rhenium complexes exhibit activity in nanomolar concentrations against Gram-positive pathogens such as <i>Staphylococcus aureus</i> strains, including methicillin-resistant <i>S. aureus</i> (MRSA) and <i>Enterococcus faecium</i>. The molecules do not affect bacterial cell membrane potential, but some of the most potent complexes strongly interact with DNA, indicating it as a possible target for their mode of action. <i>I</i><i>n vivo </i>studies in the zebrafish model showed that the complexes with anti-staphylococcal/MRSA activity were non-toxic to the organism even at much higher doses of the corresponding MICs. In the zebrafish-MRSA infection model, the complexes increased the survival rate of infected fish up to 100 % and markedly reduced bacterial burden. Moreover, all rescued fish developed normally following the treatments with the metallic compounds.</p>

Indole-containing arene-ruthenium complexes with broad spectrum activity against antibiotic-resistant bacteria

“…( Zhang et al., 2017 ) In the last decades, a wide range of inorganic and organometallic compounds have been investigated for killing or inhibiting microbial growth. ( Gambino and Otero, 2019 , Sierra et al., 2019 , Ravera et al., 2018 , Jürgens and Casini, 2017 , Lee et al., 2017 , Patil et al., 2015 , Patra et al., 2012 , Patra et al., 2015 , Smitten et al., 2020 , Smitten et al., 2020 , Sierra et al., 2019 , Frei, 2020 , Nasiri Sovari and Zobi, 2020 , Frei et al., 2020 , Frei et al., 2021 , Sovari et al., 2021 , Sovari et al., 2020 )…”

Combatting AMR: a molecular approach to the discovery of potent and non-toxic rhenium complexes active against C. albicans-MRSA co-infection

“…UV-Vis (CH3CN, nm): 329, 344. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.14 -9.17 (d, J = 3.79 Hz, 1H), 7.50 (d, J = 2.08 Hz, 1H), 7.47 -7.49 (m, 1H), 6.97 (d, J = 6.24 Hz, 1H), 6.91 -6.94 (m, 1H), 6.86 -6.89 (m, 1H), 6.81 (d, J = 5.99 Hz, 1H), 5.25 (s, 1H), 4.36 (t, J = 6.42 Hz, 1H), 4.11 (t, J = 6.05 Hz, 1H), 3.18 -3.22 (m, 1H), 3.14 (s, 2H), 3.08 (s, 3H), 2.93 (s, 3H), 2.76 -2.80 (m, 1H).…”

“…UV-Vis (CH3CN, nm): 287, 367. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.04 (d, J = 5.99 Hz, 2H), 8.64 (dd, J = 6.60, 7.46 Hz, 2H), 3.10 -3.17 (m, 5H), 3.09 -3.17 (m, 6H). fac-Re(CO) 3 NN1Im: (ReNN1Im).…”

“…UV-Vis (CH3CN, nm): 291, 362. 1 H NMR (400 MHz, acetonitrile-d3) δ 9.03 (dd, J = 0.43, 5.93 Hz, 2H), 8.39 (d, J = Embryos produced by pair-wise mating were collected and distributed into 24-well plates containing 10 embryos per well and 1 mL E3 medium (5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2 and 0.33 mM MgSO4 in distilled water) and raised at 28 °C. For assessing acute (lethality) and developmental (teratogenicity) toxicity, the embryos at 6 hours post fertilization (hpf) stage were treated with eight different concentrations of the tested compounds (50, 40, 25, 12.5, 6.25, 3.12, 1.56 and 0.78 µM), and inspected for apical endpoints (Table S1) every day by 120 hpf upon an steremicroscope (Carl Zeiss™ Stemi 508 doc Stereomicroscope, Germany).…”

“…The rise of antimicrobial resistance (AMR) and the lack of effective drugs to combat resistant strains have become major health threats to humankind. 1,2 AMR emerges much faster than new antimicrobials discovery, and usually develops a few years after a novel drug is introduced to the clinic.…”