Transition metal diamine complexes with antimicrobial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA)

Abstract

Pentaalkylcyclopentadienyl (Cp* R ) iridium (Ir) and cobalt (Co) 1,2-diamine complexes were synthesized. Susceptibility of Staphylococcus aureus and recent patient methicillin-resistant S. aureus (MRSA) isolates to the transition metal-diamine complexes were measured by broth microdilution and reported as the MIC and MBC. Hemolytic activities of the transition metal-complexes as well as toxicity toward Vero cells were also measured. The transition metal complex of Cp* R Ir with cis-1,2-diaminocyclohexane, had strong antibiotic activity against S. aureus and MRSA (MIC = 4 μg mL −1 , MBC = 8 μg mL −1 ) strains and killed 99% of S. aureus cells in 6 hours. Stronger antibiotic activity was associated with the presence of octyl linked to the cyclopentadienyl group and cyclohexane as the diamine backbone. Activity was greatly diminished by trior tetramethylation of the nitrogen of the diamine. A cyclopentadienylcobalt complex of cis-1,2-diaminocyclohexane also showed significant anti-microbial activity against both S. aureus and MRSA strains. The absence of hemolytic activity, Vero cell cytotoxicity and the significant anti-microbial activity of several members of the family of compounds reported suggest this is an area worth further development.Med. Chem. Commun. This journal is

Iridium piano stool complexes with activity againstS. aureusand MRSA: it is past time to truly think outside of the box

“…3) from the simplest 1,2diaminoethane (ethylenediamine, en) to more complicated and substituted diamines. The structure-activity relationships for (Cp* R )IrIJ1,2-diamine)Cl cations were reported previously, 26 but the overall theme would suggest some of the most important characteristics were: a) a longer hydrophobic chain on the Cp* R ring; b) increased hydrophobicity of the substituents on the 1,2-diaminoalkane, either on the nitrogen or the alkyl backbone; and, c) the presence of hydrogen-bond donors (N-H) on the diamine ligand all correlated with higher antimicrobial activity. However, there was one subtlety that will be discussed in greater detail below: a large difference in activity was found between cis-1,2-diaminocyclohexane and trans-1,2-diaminocyclohexane complexes.…”

“…23 Lately, we have reported on a class of what are known as "halfsandwich" metal complexes that can be tuned for activity against mycobacteria 24,25 as well as against S. aureus including MRSA. 26 This paper gives further details of our work on antistaph complexes including an initial toxicity screening and makes the case that, as strange as this class of compounds may seem to many practitioners in the field, it is time to be bold in a much deeper and broader examination of metal compounds. 27 2 Experimental…”

“…The syntheses of the various diamine complexes discussed in this paper have been described before. 26 All compounds are air-stable and water soluble, so no special handling techniques are needed. The best candidates of all of the diamine complexes tested were subject to a number of in vitro procedures to test for toxicity toward mammalian cells.…”

Metal Complexes, an Untapped Source of Antibiotic Potential?

“…The active iridium complexes did not show any cytotoxicity against the Vero cell line ATCC CCL-81 up to 500 µg/mL or hemolytic properties up to 250 µg/mL. Complex 24 was further described as non-toxic in mice at doses of 5 mg/kg, however no experimental details were disclosed [101]. More recently, the same authors reported a new series of piano-stool iridium diamino-type complexes that showed activity against a S. aureus as well as a MRSA strain while displaying no toxicity in vitro and in vivo (25, MICs = 5-7.5 ug/mL, Figure 9).…”

Noble Metal Organometallic Complexes Display Antiviral Activity against SARS-CoV-2

“…While the chemotherapeutic activity of similar complexes has been reported [24][25][26][27][28], as a whole, investigations into the virucidal properties of piano stool complexes are understudied. However, our own studies [29][30][31][32][33] and other reports [22,[34][35][36][37][38] have shown that organometallic piano stool complexes have robust antimicrobial activity against highly antibiotic-resistant bacteria including Mycobacterium spp. and Staphylococcus spp.…”