Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin. [1]
Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin. [1]
Lincosamides consist of a pyrrolidine ring linked to a pyranose moiety (methylthio-lincosamide) via an amide bond. [2] [3] Hydrolysis of lincosamides, specifically lincomycin, splits the molecule into its building blocks of the sugar and proline moieties. Both of these derivatives can conversely be recombined into the drug itself or a derivative. [4]
Biosynthesis of lincosamides occurs through a biphasic pathway, in which propylproline and methylthiolincosamide are independently synthesized immediately before condensation of the two precursor molecules. Condensation of the propylproline carboxyl group with the methylthiolincosamide amine group via an amide bond forms N-demethyllincomycin. N-Demethyllincomycin is subsequently methylated via S-adenosyl methionine to produce lincomycin A. [5] [6]
Lincomycin is naturally produced by bacteria species, namely Streptomyces lincolnensis , S. roseolus , and S. caelestis . [7] Clindamycin is derived via (7S)-chloro-substitution of the (7R)-hydroxyl group of lincomycin. [8] Lincomycin is primarily isolated from fermentations of Streptomyces lincolnensis, while clindamycin is prepared semi-synthetically. [9] While several hundred synthetic and semi-synthetic derivatives of lincosamides have been prepared, only lincomycin A and clindamycin are used in clinical practice due to issues with toxicity and low biological activity in other lincosamide antibiotics. [9]
Lincosamides prevent bacterial replication in a bacteriostatic mechanism by interfering with the synthesis of proteins.
In a mechanism similar to macrolides and streptogramin B, lincosamides bind close to the peptidyl transferase center on the 23S portion of the 50S subunit of bacterial ribosomes. Under the influence of high resolution X-ray, structures of clindamycin and ribosomal subunits from bacterium have previously revealed exclusive binding to the 23S segment of the peptidyl transferase cavity. [10] Binding is mediated by the mycarose sugar moiety which has partially overlapping substrates with peptidyl transferase. By extending to the peptidyl transferase center, lincosamides cause the premature dissociation of peptidyl-tRNA's containing two, three or four amino acid residues. In this case, peptides will grow to a certain point until steric hindrance inhibits peptidyl transferase activity. [11] Lincosamides do not interfere with protein synthesis in human cells (or those of other eukaryotes) due to structural differences between prokaryotic and eukaryotic ribosomes. Lincosamides are used against Gram-positive bacteria since they are unable to pass through the porins of Gram-negative bacteria.
Soon after the emergence of clinical lincosamide use in 1953, strains of resistant staphylococci were isolated in several countries including France, Japan and the United States. [13] Resistant strains were characterized by expression of methyltransferases which dimethylate residues within the 23S subunit of ribosomal RNA, preventing binding of macrolides, lincosamides and streptogramins B. The gene family responsible for encoding of these methyltransferases is referred to as the "erm" family, or erythromycin ribosome methylase family of genes. [14] Nearly 40 erm genes have been reported to date, which are transferred primarily through plasmids and transposons. [15]
Several strains of bacteria which are highly resistant to macrolide treatment have been isolated and found to possess mutations at the transferase binding pocket in the 23S ribosomal subunit. Macrolide-resistant Streptococcus pneumoniae isolated from hospital patients in Eastern Europe and North America were found to contain mutations in either 23S or other ribosomal protein genes. [16]
Gram-negative bacteria harbor genes encoding for molecular pumps which can contribute to resistance of hydrophobic compounds like macrolides and lincosamides. [14] Out of the many families of multidrug resistance pumps, lincosamides are most commonly shunted through pumps belonging to the resistance-nodulation-cell division superfamily. [17] Staphylococci express efflux pumps with specificity for 14 and 15 member ring macrolides and streptogramin B, but not lincosamide molecules. [18]
Clinical isolates of S. aureus harboring genes which encode for lincosamide nucleotransferases have been reported. Genes lnuA and lnuB confer resistance to lincomycin, but not clindamycin. These genes, however, limit the bacteriostatic activity of clindamycin. [15] This type of resistance is rare in S. aureus, but has been reported to be more prevalent in other bacteria strains. [19]
Approximately 90% of orally administered lincosamides are absorbed, with slight variance depending on which drug is given. Plasma concentrations via this route peak within 2–4 hours. Intramuscular administration of lincosamides results in strong absorption, with peak plasma levels being reached in 1–2 hours. Around 90% of clindamycin is bound to plasma proteins, and is generally more stable and rapidly absorbed than lincomycin. [20]
Lincosamides have a broad distribution in several tissues, excluding cerebrospinal fluid. When administered intramuscularly to rats, lincomycin was found to accumulate in highest concentrations in the kidneys when compared to other tissues, while clindamycin was found in highest concentrations within the lungs. [21] Clindamycin accumulates in macrophages and other white blood cells, which can result in concentrations 50 times higher than plasma levels. [22]
Lincosamides are often used clinically as an alternative antibiotic for patients who are allergic to penicillin. Of the lincosamides, clindamycin is most commonly used within the clinic due to its higher bioavailability, higher oral absorption and efficacy within the target organism spectrum. [23] Lincosamides are generally the first-choice use antibiotic class in veterinary microbiology, most commonly used to combat skin infections. [7]
Potential clinical uses for lincosamide antibiotics in humans are numerous. They are efficacious in the treatment of dental infections, abdominal infections, abscesses, pelvic inflammatory disease and anaerobic infections. Clindamycin alone has been shown to be efficacious in the treatment of acne, [24] toxic shock syndrome [25] and malaria, [26] and to decrease the risk of premature births in women with bacterial vaginosis. [27] Lincosamide antibiotics may also be useful in the treatment of methicillin-resistant S. aureus. [28]
While there have been no reports of severe organ toxicity from lincosamide treatment, gastrointestinal disturbances have been associated with their administration. Pseudomembranous enterocolitis resulting from clindamycin-induced disruption of gastrointestinal flora can be a lethal adverse event observed in several species when used in the veterinary clinic, particularly in horses. At extremely high doses of clindamycin, skeletal muscle paralysis has been demonstrated in several species. Lincosamides can interact with anesthetic agents to produce neuromuscular effects. [29]
Other adverse reactions include diarrhea, nausea, vomiting, abdominal pain and rash. Topical administration of clindamycin may induce contact dermatitis, dryness, burning, itching, scaliness and peeling of the skin. [30]
The first lincosamide compound discovered was lincomycin, isolated from Streptomyces lincolnensis in a soil sample from Lincoln, Nebraska (hence the bacterial name). [2]
Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products. Some macrolides have antibiotic or antifungal activity and are used as pharmaceutical drugs. Rapamycin is also a macrolide and was originally developed as an antifungal, but is now used as an immunosuppressant drug and is being investigated as a potential longevity therapeutic.
Enterococcus is a large genus of lactic acid bacteria of the phylum Bacillota. Enterococci are gram-positive cocci that often occur in pairs (diplococci) or short chains, and are difficult to distinguish from streptococci on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90–95%) and E. faecium (5–10%). Rare clusters of infections occur with other species, including E. casseliflavus, E. gallinarum, and E. raffinosus.
Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.
Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.
Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.
The peptidyl transferase is an aminoacyltransferase as well as the primary enzymatic function of the ribosome, which forms peptide bonds between adjacent amino acids using tRNAs during the translation process of protein biosynthesis. The substrates for the peptidyl transferase reaction are two tRNA molecules, one bearing the growing peptide chain and the other bearing the amino acid that will be added to the chain. The peptidyl chain and the amino acids are attached to their respective tRNAs via ester bonds to the O atom at the CCA-3' ends of these tRNAs. Peptidyl transferase is an enzyme that catalyzes the addition of an amino acid residue in order to grow the polypeptide chain in protein synthesis. It is located in the large ribosomal subunit, where it catalyzes the peptide bond formation. It is composed entirely of RNA. The alignment between the CCA ends of the ribosome-bound peptidyl tRNA and aminoacyl tRNA in the peptidyl transferase center contribute to its ability to catalyze these reactions. This reaction occurs via nucleophilic displacement. The amino group of the aminoacyl tRNA attacks the terminal carboxyl group of the peptidyl tRNA. Peptidyl transferase activity is carried out by the ribosome. Peptidyl transferase activity is not mediated by any ribosomal proteins but by ribosomal RNA (rRNA), a ribozyme. Ribozymes are the only enzymes which are not made up of proteins, but ribonucleotides. All other enzymes are made up of proteins. This RNA relic is the most significant piece of evidence supporting the RNA World hypothesis.
Lincomycin is a lincosamide antibiotic that comes from the actinomycete Streptomyces lincolnensis. A related compound, clindamycin, is derived from lincomycin by using thionyl chloride to replace the 7-hydroxy group with a chlorine atom with inversion of chirality. It was released for medical use in September 1964.
Klebsiella oxytoca is a Gram-negative, rod-shaped bacterium that is closely related to K. pneumoniae, from which it is distinguished by being indole-positive; it also has slightly different growth characteristics in that it is able to grow on melezitose, but not 3-hydroxybutyrate. It was first described in 1886 when it was isolated from sour milk and named Bacillus oxytocus perniciosus.
Pluralibacter gergoviae is a Gram-negative, motile, facultatively-anaerobic, rod-shaped bacterium. P. gergoviae is of special interest to the cosmetics industry, as it displays resistance to parabens, a common antimicrobial agent added to cosmetic products.
The 23S rRNA is a 2,904 nucleotide long component of the large subunit (50S) of the bacterial/archean ribosome and makes up the peptidyl transferase center (PTC). The 23S rRNA is divided into six secondary structural domains titled I-VI, with the corresponding 5S rRNA being considered domain VII. The ribosomal peptidyl transferase activity resides in domain V of this rRNA, which is also the most common binding site for antibiotics that inhibit translation, making it a target for ribosomal engineering. A well-known member of this antibiotic class, chloramphenicol, acts by inhibiting peptide bond formation, with recent 3D-structural studies showing two different binding sites depending on the species of ribosome. Numerous mutations in domains of the 23S rRNA with Peptidyl transferase activity have resulted in antibiotic resistance. 23S rRNA genes typically have higher sequence variations, including insertions and/or deletions, compared to other rRNAs.
A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.
Streptogramin A is a group of antibiotics within the larger family of antibiotics known as streptogramins. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds while group B antibiotics are depsipeptides. While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.
The P-site is the second binding site for tRNA in the ribosome. The other two sites are the A-site (aminoacyl), which is the first binding site in the ribosome, and the E-site (exit), the third. During protein translation, the P-site holds the tRNA which is linked to the growing polypeptide chain. When a stop codon is reached, the peptidyl-tRNA bond of the tRNA located in the P-site is cleaved releasing the newly synthesized protein. During the translocation step of the elongation phase, the mRNA is advanced by one codon, coupled to movement of the tRNAs from the ribosomal A to P and P to E sites, catalyzed by elongation factor EF-G.
The Eagle effect, Eagle phenomenon, or paradoxical zone phenomenon, named after Harry Eagle who first described it, originally referred to the paradoxically reduced antibacterial effect of penicillin at high doses, though recent usage generally refers to the relative lack of efficacy of beta lactam antibacterial drugs on infections having large numbers of bacteria. The former effect is paradoxical because the effectiveness of an antibiotic generally rises with increasing drug concentration.
Finegoldia is a genus of Gram-positive bacteria. They are anaerobic cocci of the class Clostridia, with Finegoldia magna being the type species. F. magna was formerly known, along with several other Gram-positive anaerobic cocci (GPACs), as Peptostreptococcus magnus, but was moved into its own genus in 1999. The name is in honor of Sydney M. Finegold, an American microbiologist, while magna is Latin for large. It is an opportunistic human pathogen that normally colonizes skin and mucous membranes. It is often seen in biofilms on chronic ulcers such as in diabetic foot or decubitus ulcers. Most surveys have found it to be susceptible to penicillins, carbapenems and metronidazole, though resistant strains have been identified. Resistance to clindamycin is common and has been seen in over 10% of isolates in the US. One review stated that "the combination of diminished antimicrobial susceptibility, its prevalence, and the described virulence factors gives F. magna a special position among the GPAC."
Kluyvera is a Gram negative, facultatively anaerobic bacterial and motile genus from the family of Enterobacteriaceae which have peritrichous flagella. Kluyvera occur in water, soil and sewage. Kluyvera bacteria can cause opportunistic infections in immunocompromised patients.
Mustard is a database that tracks Antimicrobial Resistance Determinants (ARDs). The method by which it tracks ARDs is using their own method adapted from Protein Homology Modelling called Pairwise Comparative Modelling (PCM), which increase specificity protein prediction, especially for distantly related protein homologues. Using PCM, 6095 ARDs from 20 families in the human gut microbiota. Antibiotic resistance databases used were ResFinder, ARG-ANNOT, the now defunct Lahey Clinic, Marilyn Roberts website for tetracycline and macrolide resistance genes and metagenomics.
Karen Bush is an American biochemist. She is a Professor of Practice in Biology at Indiana University and the interim director of the Biotechnology program. Bush conducts research focusing on bacterial resistance mechanisms to beta-lactam antibiotics.
Multidrug-resistant bacteria are bacteria that are resistant to three or more classes of antimicrobial drugs. MDR bacteria have seen an increase in prevalence in recent years and pose serious risks to public health. MDR bacteria can be broken into 3 main categories: Gram-positive, Gram-negative, and other (acid-stain). These bacteria employ various adaptations to avoid or mitigate the damage done by antimicrobials. With increased access to modern medicine there has been a sharp increase in the amount of antibiotics consumed. Given the abundant use of antibiotics there has been a considerable increase in the evolution of antimicrobial resistance factors, now outpacing the development of new antibiotics.
Karen Joy Shaw is an American microbiologist and discoverer of novel antifungal and antibacterial compounds. She is best known for her work on aminoglycoside resistance in bacteria as well as leading drug discovery research teams. As Senior Vice President of Biology at Trius Therapeutics, Inc. her work was critical to the development of the oxazolidinone antibiotic tedizolid phosphate (Sivextro) as well as the discovery of the TriBE inhibitors, a novel class of DNA gyrase/Topoisomerase IV antibacterial agents that target both Gram-positive and Gram-negative organisms.[2] As Chief Scientific Officer at Amplyx Pharmaceuticals, Shaw was responsible for the preclinical development of the novel antifungal fosmanogepix, a first-in-class broad-spectrum antifungal prodrug that is currently in Phase 2 clinical development for the treatment of invasive fungal infections. She also discovered APX2039, a unique Gwt1 inhibitor that is in preclinical development for the treatment of cryptococcal meningitis.