The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or “caliche pits”, located in Kerrville, Texas. The sample was collected by a scientist employed by Lederle Labs (now part of Pfizer) while on vacation1.
Calicheamicin γ1 is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML).
A second calicheamicin-linked monoclonal antibody, inotuzumab ozogamicin (marketed as Besponsa) an anti-CD22-directed antibody-drug conjugate, was approved by the U.S. Food and Drug Administration on August 17, 2017, for use in the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.
Calicheamicin displays unbiased toxicity to bacteria, fungi, viruses, and eukaryotic cells and organisms, which raises questions as to how the calicheamicin-producing Micromonospora manages not to poison itself.
An answer to this question was presented in 2003 when Thorson and coworkers presented the first known example of a “self-sacrifice” resistance mechanism encoded by the gene calC from the calicheamicin biosynthetic gene cluster2. In this study, the scientists revealed calicheamicin to cleave the protein CalC site-specifically, destroying both the calicheamicin and the CalC protein, thereby preventing DNA damage.
The same group went on to solve the structure of CalC and, more recently, in collaboration with scientists from the Center for Pharmaceutical Research and Innovation (CPRI), discover structural or functional homologs encoded by genes in the calicheamicin gene cluster previously listed as encoding unknown function3.
In this latter study, the authors suggest that CalC homologs may serve in a biosynthetic capacity as the long-sought-after polyketide cyclases required to fold or cyclize early intermediates en route to calicheamicin.
Calicheamicins target DNA and cause strand scission. Calicheamicins bind with DNA in the minor groove, wherein they then undergo a reaction analogous to the Bergman cyclization to generate a diradical species.
This diradical, 1,4-didehydrobenzene, then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which ultimately leads to strand scission. The specificity of binding of calicheamicin to the minor groove of DNA was demonstrated by Crothers et al. (1999) to be due to the aryltetrasaccharide group of the molecule.
Maiese WM, Lechevalier MP, Lechevalier HA, Korshalla J, Kuck N, Fantini A, Wildey MJ, Thomas J, Greenstein M. Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties. J Antibiot (Tokyo). 1989 Apr;42(4):558-63. ↩︎
Biggins, JB; Onwueme, KC; Thorson, JS (Sep 12, 2003). Resistance to enediyne antitumor antibiotics by CalC self-sacrifice. Science. 301 (5639): 1537–41. ↩︎
Elshahawi, SI; Ramelot, TA; Seetharaman, J; Chen, J; Singh, S; Yang, Y; Pederson, K; Kharel, MK; Xiao, R; Lew, S; Yennamalli, RM; Miller, MD; Wang, F; Tong, L; Montelione, GT; Kennedy, MA; Bingman, CA; Zhu, H; Phillips GN, Jr; Thorson, JS (Aug 13, 2014). Structure-Guided Functional Characterization of Enediyne Self-Sacrifice Resistance Proteins, CalU16 and CalU19. ACS Chemical Biology. 9 (10): 2347–58 ↩︎