Metal complexes as a promising source for new antibiotics

Abstract

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.

Fig. 1. Periodic table highlighting the elements classified as metals for the purpose of this study (white) and the subset of these elements that are contained in compounds that have been submitted to CO-ADD to date (orange). Figure adapted with permission from Nessa Carson (www.supersciencegrl.co.uk).

Fig. 2. (A) Elemental distribution of all 906 metal-containing compounds submitted to CO-ADD (black); 246/906 submitted metal-containing compounds with at least one MIC lower or equal to 16 μg mL^–1 or 10 μM (red) against the tested organisms; 88/246 active metal-containing compounds with no cytotoxicity or hemolytic activity at the highest concentration tested (blue). (B) Metal frequency amongst the 906 metal-containing compounds submitted to CO-ADD. (C) Metal frequency amongst the 246 metal complexes that possess some activity against the tested organisms. (D). Metal frequency amongst the 88 compounds that are active as well as ‘non-toxic’ (see text for definition). (E) Percentage of submitted metal-containing compounds with antimicrobial activity, compared to the overall hit rate for organic compounds within the CO-ADD collection.

Fig. 3. (A) Percentage of submitted compounds that were found to be active, classified by element. (B) Percentage of submitted compounds that were found to be active and ‘non-toxic’, classified by compounds per element that are also non-toxic. (C) Overall success-rate of compounds, classified by element.

Fig. 4. Activity distribution of metal complexes between the different classes of bacteria (left) and as distribution of the MIC for S. aureus (MRSA, ATCC 43300) and E. coli (ATCC 25922) shown as box plot (first and third quartile) with median (line), mean (cross) and outliers (dots).

Fig. 5. Structures of metal complexes that showed activity against strains and were not toxic and/or haemolytic to mammalian cells at the same concentration.