The Gentamicin Complex


Gentamicin sulfate is an aminoglycoside antibiotic composed of several related gentamicin fractions or congeners and is used clinically to combat infections caused by Gram-negative bacteria. The main and most bioactive congeners of gentamicin include members of the gentamicin C complex. Gentamicin A, B, and X have lower bioactivity than the gentamicin C complex. Pharmaceutical grade gentamicin that conforms to United States Pharmacopoeia (USP) and European Pharmacopoeia (EP) specifications generally consists of the gentamicin C complex (~80%), and the A, B, and X complexes (~20%). [1]

Because of its higher bioactivity, the gentamicin C complex has been studied more aggressively than the other gentamicin components. It consists largely of congeners gentamicin C1 and gentamicin C1a and enantiomers gentamicin C2 and gentamicin C2a. There are a few minor constituents of this complex, including gentamicin C2b. Gentamicin C2a in particular has not been well researched. Due to the difficult process of separating it, it is not offered by many other suppliers. Bioactivity tests have shown only minor differences between each of the gentamicin C congeners. [2]

Most aminoglycoside antibiotics, including gentamicin, are toxic to the kidneys and are referred to as nephrotoxic, or having renal toxicity. As mentioned above gentamicin is needed to fight off Gram-negative bacterial infections; however, its efficacy comes with a worryingly high rate of renal injury. Recent research has focused on determining whether or not some gentamicin congeners are characterized by low nephrotoxicity but retain antibacterial efficacy. Gentamicin C2 in particular has shown little to no signs of cytotoxicity in vitro and equally little nephrotoxicity in an in vivo rat model. [3]

Nephrotoxicity can also be affected by the variable pharmacokinetics of the gentamicin C complex. Gentamicin is unique in that it does not undergo metabolism, but rather, is removed by glomerular filtration. Aminoglycoside nephrotoxicity can be attributed to the uptake of the drug into renal tubular cells, so the clearance time of each congener in vivo may contribute to their differential toxicity. Researchers found gentamicin C1a to have significantly higher clearance in a horse model, and gentamicin C1 to have higher clearance in dogs. [4] [5] If one fraction is found to clear more quickly in humans, it could potentially reduce gentamicin related renal toxicity.

Clinical gentamicin complex has also shown ototoxicity, causing permanent auditory system damage. Gentamicin C1, however, has shown less ototoxicity. [6] More toxicity studies on the gentamicin fractions would be needed to create a safer clinical gentamicin consisting of only the least toxic congeners, to increase safety with no cost to bactericidal efficacy.

Gentamicin X2’s bioactivity has not been thoroughly researched, but it is well known as the precursor component to the very bioactive gentamicin C complex. The graphic below was obtained from a paper by Gu et al. and illustrates the biosynthetic scheme of the gentamicin C complex from Gentamicin X2 [7]:



Studying the individual congeners of gentamicin allows us to fully explore the potential of gentamicin and is a promising way to increase its safety and therapeutic window. Similar research is being done with other antibiotic congeners and we hope to see exciting data in the future!

Resources:

[1] Vydrin, A. F., Shikhaleev, I. V., Makhortov, V. L., Shcherenko, N. N., & Kolchanova, N. V. (2003). Component Composition of Gentamicin Sulfate Preparations. Pharmaceutical Chemistry Journal, 37(8), 448-450. doi.org/10.1023/A:1027372416983

[2] Weinstein, M. J., Wagman, G. H., Oden, E. M., & Marquez, J. A. (1967). Biological activity of the antibiotic components of the gentamicin complex. Journal of Bacteriology, 94(3), 789–790.

[3] Sandoval, R. M. (2006). A Non-Nephrotoxic Gentamicin Congener That Retains Antimicrobial Efficacy. Journal of the American Society of Nephrology, 17(10), 2697-2705. doi.org/10.1681/asn.2005101124

[4] Isoherranen, N., Lavy, E., & Soback, S. (2000). Pharmacokinetics of Gentamicin C1, C1a, and C2 in Beagles after a Single Intravenous Dose. Antimicrobial Agents and Chemotherapy, 44(6), 1443-1447. doi.org/10.1128/aac.44.6.1443-1447.2000

[5] Steinman, A., Isoherranen, N., Ashoach, O., & Soback, S. (2010). Pharmacokinetics of gentamicin C1, C1a and C2 in horses after single intravenous dose. Equine Veterinary Journal, 34(6), 615-618. doi.org/10.2746/042516402776180160

[6] Fox, K. E., Brummett, R. E., & Brown, R. (1980). A Comparative Study of the Ototoxicity of Gentamicin and Gentamicin C1. Archives of Otolaryngology - Head and Neck Surgery, 106(1), 44-49. doi.org/10.1001/archotol.1980.00790250046009

[7] Gu, Y., Ni, X., Ren, J., Gao, H., Wang, D., & Xia, H. (2015). Biosynthesis of Epimers C2 and C2a in the Gentamicin C Complex. ChemBioChem, 16(13), 1933-1942. doi.org/10.1002/cbic.201500258