Antibiotic inhibitors of the peptidyl transferase center. 1. clindamycin as a composite analogue of the transfer RNA fragments L-Pro-Met and the D-ribosyl ring of adenosine

doi:10.1016/S0960-894X(97)10196-2

Bioorganic & Medicinal Chemistry Letters

Volume 8, Issue 1, 6 January 1998, Pages 87-92

https://doi.org/10.1016/S0960-894X(97)10196-2 Get rights and content

Abstract

Clindamycin's three-dimensional structure is shown via a computer rendered stereomodel to be strikingly similar to L-Pro-Met and the D-ribosyl ring of adenosine. This discovery has important implications for the rational design of new lincosamides and for efforts to understand how this and related classes of agents selectively inhibit protein biosynthesis on the prokaryotic ribosome.

The widely used antibiotic clindamycin (1) is shown via a computer-generated stereomodel to resemble L-Pro-Met and the D-ribosyl ring of adenosine, residues which occur at the 3′-ends of certain peptidyl- and deacylated-tRNAs.

References (34)

J.R. Black et al.
Eur. J. Clin. Microbiol. Infect. Dis.
(1991)
B.J. Magerlein
Adv. Appl. Microbiol.
(1971)
S. Kirillov et al.
FEBS Letters
(1997)
M.L. Celma et al.
FEBS Letters
(1970)
M.L. Celma et al.
FEBS Letters
(1971)
R.J. Harris et al.
Bioorg. Chem.
(1973)
S. Kallia-Raftopoulos et al.
Arch. Biochem. Biophys.
(1992)
R.D. Birkenmeyer et al.
Antimicrob. Ag. Chemother.
(1966)
R.D. Birkenmeyer et al.
J. Med. Chem.
(1970)
B.J. Magerlein et al.
J. Med. Chem.
(1969)

A. Kucers et al.

J. Blais et al.

Antimicrob. Agts. Chemother.

(1993)

C.J.M. Beckers et al.

J. Clin. Invest.

(1995)

P.G. Kremsner

J. Antimicrob. Chemother.

(1990)

F.N. Chang et al.

Biochemistry

(1967)

B. Weisblum et al.

Bacteriol. Rev.

(1968)

W. Morozowich

U.S. Patent No. 3,853,843

(1974)

Cited by (15)

Degradation of lincomycin in aqueous solution with hydrothermal treatment: Kinetics, pathway, and toxicity evaluation
2018, Chemical Engineering Journal
Citation Excerpt :
Regarding lincomycin, pyranose ring (Fig. S1) is active moiety that inhibited proteins biosynthesis. Its inhibition effect could decline by almost 100-fold when one or more of the three hydroxyl groups in pyranose ring were disrupted or replaced [16]. Similarly, the oxidation or replacement of methylthio in pyranose rings could also result in significant losses of inhibition [16].
Recently, lincomycin has been detected frequently in aquatic environment, especially in the effluent of pharmaceutical wastewater treatment plants. Public concerns have been raised due to its adverse bio-effect and potential of inducing resistance genes. In this study, hydrothermal treatment (HT) was applied to remove lincomycin from high-concentrated pharmaceutical waste water. Influence factors (e.g., temperature, initial concentration and pH) were investigated from kinetics perspective. Meanwhile, degradation byproducts were identified using liquid chromatography–mass spectrometry (LC–MS), based on that transformation pathways were proposed. Finally, the toxicity of lincomycin degradation intermediates were evaluated by Microcystis cells. The results showed that lincomycin was eliminated efficiently via HT and an obvious lag time existed in its degradation process. An autocatalytic model was developed successfully based on the degradation kinetics analysis. The model showed good fitness with experiments data (R² > 0.99). Observed reaction constant (k) increased when reaction temperature varied from 110 to 160 °C; it decreased from 0.034 to 0.015 min⁻¹ as pH ranged from 2.0 to 6.0. Additionally, increasing initial concentration of lincomycin promoted its degradation, while it showed a different trend once the concentration exceeded 300 mg L⁻¹. A total of 7 major intermediates were identified, based on which hydrolysis, hydroxylation and desulfuration were inferred as the mainly evolution processes. Finally, toxicity evaluation indicated that both lincomycin and its degradation byproducts have no inhibition on algal strains. Thus, it is concluded that HT is an efficient method for removing lincomycin.
Acidic hydrothermal treatment: Characteristics of organic, nitrogen and phosphorus releasing and process optimization on lincomycin removal from lincomycin mycelial residues
2018, Chemical Engineering Journal
Citation Excerpt :
The diameters of inhibition circles formed by lincomycin before treatment were significantly decreased compared with that after AHT, indicating intermediates of lincomycin in AHT process with less inhibition on bacteria. In addition, the inhibition effect of lincomycin could decline by almost 100-fold when one or more of the three hydroxyl groups in its pyranose rings were disrupted or replaced [38]. Similarly, the oxidation or replacement of methylthio in pyranose rings could also result in significant losses of inhibition [38].
Lincomycin mycelial residues (LMRs), one kind of bio-wastes with a high biomass organic content, are limited to use due to residual lincomycin. Recycling of LMRs is not only benefit to economy but also to environment. This study developed an acidic hydrothermal method for LMRs treatment. Effects of reaction temperature (100, 130 and 160 °C), residence time (60, 120 and 180 min), and H₂SO₄ concentration (0.2, 0.4 and 0.6 M) on the amount and distributions of organics, nitrogen and phosphorus were investigated. In addition, these three crucial parameters for maximum removal of lincomycin were optimized using response surface methodology (RSM). Meanwhile, intermediates of lincomycin treated by acidic hydrothermal treatment (AHT) were identified by liquid chromatography – mass spectrometry (LC/MS). Antibacterial assessments of them were conducted via disk diffusion tests. Results showed that the treatments led to 34.7%–251% and 30.9%–214% in the concentrations of TN and TP, respectively, and 1.44–3.89 times higher of SCOD in the soluble phase of LMRs. Lincomycin removal rates increased with the increasing of reaction temperature, residence time and H₂SO₄ concentration in a certain range. The optimal conditions were obtained at activation temperature of 160 °C, residence time of 157.2 min and a H₂SO₄ concentration of 0.53 M, where 98.3% of lincomycin was removed. Moreover, inhibition of lincomycin after AHT on Staphyococcus aureus, with respect to untreated solutions containing this compound reduced significantly. Therefore, recycling of LMRs is promising after removal residual lincomycin via AHT.
Structure and Mechanism of the Lincosamide Antibiotic Adenylyltransferase LinB
2009, Structure
Citation Excerpt :
It is mostly active against gram-positive organisms, but also finds use against selected gram-negative anaerobes and protozoa. These antibiotics function by blocking microbial protein synthesis via binding to the 23S rRNA of the 50S subunit and mimicking the intermediate formed in the initial phase of the elongation cycle (Schlunzen et al., 2001; Fitzhugh, 1998). The most clinically relevant lincosamide, clindamycin, is frequently used to treat infections caused by streptococci and staphylococci.
Lincosamides make up an important class of antibiotics used against a wide range of pathogens, including methicillin-resistant Staphylococcus aureus. Predictably, lincosamide-resistant microorganisms have emerged with antibiotic modification as one of their major resistance strategies. Inactivating enzymes LinB/A catalyze adenylylation of the drug; however, little is known about their mechanistic and structural properties. We determined two X-ray structures of LinB: ternary substrate– and binary product–bound complexes. Structural and kinetic characterization of LinB, mutagenesis, solvent isotope effect, and product inhibition studies are consistent with a mechanism involving direct in-line nucleotidyl transfer. The characterization of LinB enabled its classification as a member of a nucleotidyltransferase superfamily, along with nucleotide polymerases and aminoglycoside nucleotidyltransferases, and this relationship offers further support for the LinB mechanism. The LinB structure provides an evolutionary link to ancient nucleotide polymerases and suggests that, like protein kinases and acetyltransferases, these are proto-resistance elements from which drug resistance can evolve.
Unraveling new features of clindamycin interaction with functional ribosomes and dependence of the drug potency on polyamines
2006, Journal of Biological Chemistry
Citation Excerpt :
In conclusion, although the values of the kinetic parameters determined here might differ somewhat from the in vivo situation, the use of puromycin is appropriate to investigate the mechanism of clindamycin interaction with ribosomes. Our results cannot support functional correlation of clindamycin with transition-state substrates or hypothetical intermediates in the peptide elongation cycle, as proposed by other studies (14-16). Both the dissociation constant (Ki) for the encounter complex CI and the apparent dissociation constant (k7/kassoc) for the final complex C*I are much higher than the Kd predicted for the transition state of the PTase-catalyzed puromycin reaction (38).
The effect of spermine on the inhibition of peptide-bond formation by clindamycin, an antibiotic of the Macrolide-Lincosamide-Streptogramins_B family, was investigated in a cell-free system derived from Escherichia coli. In this system peptide bond is formed between puromycin, a pseudo-substrate of the A-site, and acetylphenylalanyl-tRNA, bound at the P-site of poly(U)-programmed 70 S ribosomes. Biphasic kinetics revealed that one molecule of clindamycin, after a transient interference with the A-site of ribosomes, is slowly accommodated near the P-site and perturbs the 70 S/acetylphenylalanyl-tRNA complex so that a peptide bond is still formed but with a lower velocity compared with that observed in the absence of the drug. The above mechanism requires a high temperature (25 °C as opposed to 5 °C). If this is not met, the inhibition is simple competitive. It was found that at 25 °C spermine favors the clindamycin binding to ribosomes; the affinity of clindamycin for the A-site becomes 5 times higher, whereas the overall inhibition constant undergoes a 3-fold decrease. Similar results were obtained when ribosomes labeled with N¹-azidobenzamidinospermine, a photo-reactive analogue of spermine, were used or when a mixture of spermine and spermidine was added in the reaction mixture instead of spermine alone. Polyamines cannot compensate for the loss of biphasic kinetics at 5 °C nor can they stimulate the clindamycin binding to ribosomes. Our kinetic results correlate well with photoaffinity labeling data, suggesting that at 25 °C polyamines bound at the vicinity of the drug binding pocket affect the tertiary structure of ribosomes and influence their interaction with clindamycin.
Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications
2004, Advances in Applied Microbiology
Natural lincosamides are produced by several Streptomyces species, mainly by Streptomyces lincolnensis, S. roseolus, and S. caelestis and by Micromonospora halophytica. Lincosamides constitute a relatively small group of antibiotics with a chemical structure consisting of amino acid and sugar moieties. Their mechanism of action is via inhibition of protein synthesis in sensitive micro-organisms. Lincosamides have an unusual antimicrobial spectrum, being active against only Gram-positive and not Gram-negative aerobic bacteria. They exhibit a significant antibiotic activity against some anaerobic bacteria. They are used therapeutically, especially in cases where synergistic effects of a mixed anaerobic and aerobic microflora are anticipated. Lincomycin and clindamycin are also useful alternatives to penicillin and its derivatives in the treatment of upper respiratory tract infections in patients with allergy to penicillin. The chapter also discusses the major route of resistance to lincosamides. Furthermore, with the current knowledge of gene clusters specifying biosynthesis of lincomycin and the related antibiotic celesticetin, production of new derivatives of lincosamides by genetic engineering can be easily imagined, resulting in production of new derivatives of lincosamides.
Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond
2022, Antibiotics

View all citing articles on Scopus

View full text

Antibiotic inhibitors of the peptidyl transferase center. 1. clindamycin as a composite analogue of the transfer RNA fragments L-Pro-Met and the D-ribosyl ring of adenosine

Abstract

Eur. J. Clin. Microbiol. Infect. Dis.

Adv. Appl. Microbiol.

FEBS Letters

FEBS Letters

FEBS Letters

Bioorg. Chem.

Arch. Biochem. Biophys.

Antimicrob. Ag. Chemother.

J. Med. Chem.

J. Med. Chem.

Antimicrob. Agts. Chemother.

J. Clin. Invest.

J. Antimicrob. Chemother.

Biochemistry

Bacteriol. Rev.

U.S. Patent No. 3,853,843