What are tetracycline antibiotics?

Inhibiting bacterial protein synthesis by binding to the 30S ribosomal subunit is a well-known characteristic of tetracycline antibiotics, a family of broad-spectrum medicines. A crucial mechanism for bacterial growth and multiplication is blocked when this binding hinders the attachment of aminoacyl-tRNA to the mRNA-ribosome complex. As a result, the addition of amino acids to developing peptide chains comes to a grinding halt. Tetracyclines are used to treat a variety of infectious disorders because of their wide-spectrum action, which makes them effective against a wide range of bacterial infections.

By passing via the outer membrane's OmpF and OmpC porin channels, tetracyclines can enter the digestive tracts of gram-negative bacteria. Coordination complexes containing positively charged cations, probably magnesium, are formed in this complicated process. The antibiotic-metal ion combination that forms is then attracted to the electrical potential gradient across the cell membrane and eventually builds up in the periplasm. In this area, the dissociation of the metal ion-tetracycline complex is expected to occur, leading to the release of the uncharged tetracycline. Tetracycline, a molecule with minimal lipid affinity, effortlessly traverses the lipid bilayer regions of the inner membrane. One possible species that gram-positive bacteria let to get through their cytoplasmic membrane is the electroneutral and lipophilic form. The energy-dependent translocation of tetracyclines across the outer layer of the cytoplasm is aided by the proton motive force's pH discrepancy (ΔpH). Because of the greater internal pH and quantities of divalent metal ions relative to the exterior environment, tetracycline molecules are more likely to chelate within the cytoplasm. The ribosome-binding active drug species probably contains magnesium and tetracycline. Tetracyclines' bacteriostatic effects as antibiotics can be explained by their reversible connection with the ribosome.

The common chemical structure of Tetracyclines. (Rusu A, et al., 2021)

Names of tetracycline antibiotics

Tetracycline antibiotics are highly utilised in several medical areas, their action on bacterial protein synthesis gives them an asset in the battle against respiratory infections. Teracyclines, especially minocycline and doxycycline, have an essential role in the management of acne and rosacea, two skin disorders that are frequently worsened by bacteria. By eliminating the infectious bacteria responsible for chlamydia and other STDs, they also aid in the treatment of these conditions.

The earliest known tetracycline compounds were chlortetracycline and oxytetracycline. Streptomyces aureofaciens and Streptomyces rimosus were the respective organisms that produced these chemicals. Methacycline, doxycycline, and minocycline are synthetic tetracyclines; tetracycline and demethylchlortetracycline are naturally occurring tetracyclines; and S. viridofaciens, Staphylococcus aureofaciens, and S. rimosus are tetracyclines. Even though the first tetracyclines worked, scientists wanted to find analogues that would be easier to inject or swallow and have better water solubility. Using these techniques, the semisynthetic compounds lymecycline and rolitetracycline were synthesized. The most recent tetracyclines to be discovered are glycylcyclines, a class of semi-synthetic chemicals. The chemicals 9-(N,N-dimethylglycylamido)-6-demethyl-6-deoxytetracycline, 9-(N,N-dimethylglycylamido)-minocycline, and 9-t-(butylglycylamido)-minocycline are examples of these. The molecules in question include a 9-glycylamido substituent.

Tetracycline structures are labeled with generic names. (Grossman T H, 2016)

Tetracycline antibiotics at BOC Sciences

Tetracycline antibiotics classification

The classification of tetracycline antibiotics is determined by their chemical structure and production, as seen in the figures below.

(a) The tetracyclines, chlortetracycline, and oxytetracycline are one example of the first-generation tetracyclines. Their wide range of medicinal uses includes the treatment of acne, cholera, and brucellosis, among many others.

(b) Second-generation tetracyclines, including lymecycline, minocycline, and doxycycline, are more effective than first-generation tetracyclines against a broader range of microbes. A number of illnesses, including Lyme disease, pneumonia, and UTIs, can be effectively treated with it due to its prolonged half-life and much improved absorption. Their ability to penetrate tissues effectively makes them beneficial against some long-term illnesses.

(c)The third generation of tetracyclines—tigecycline, omadacycline, sarecycline, and eravacycline—were created to overcome bacterial resistance to the tetracyclines that came before them. Antibiotics that do not work against many different types of bacteria that have developed resistance to other antibiotics are usually reserved for the most severe cases of illness.

Mere discovery of tiegecycline as a synthetic minocycline derivative occurred in 1993. The first tetracycline to be used therapeutically was tigecycline, which was not introduced for over 30 years. This leads us to believe that tigecycline represents a new subclass of tetracyclines. An advantage of this new tetracycline is that it is more effective than previous versions against Gram-positive and Gram-negative bacteria that have developed resistance to several drugs. The adverse effect of tigecycline's low bioavailability is that it can only be administered intravenously.

Aminomethylcycline is the first member of the tetracycline subclass, which includes omadacycline and several more newer agents. Evidence of its wide spectrum of activity includes in vitro effectiveness against atypical bacteria, Gram-negative and Gram-positive bacteria, anaerobic bacteria, and other types of bacteria. Even more impressively, this chemical can inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, and multidrug-resistant Streptococcus pneumoniae.

Total synthesised fluorocycline eravacycline has a basic chemical structure typical of the tetracyclines class. And the naphtacen nucleus's D ring underwent certain targeted modifications as well. With these chemical tweaks, it becomes very effective against both Gram-positive and Gram-negative bacteria, including those that have evolved resistance to the tetracycline antibiotic family. This makes it ideal for treating complex intra-abdominal infections in adults. It is available in the US and several European nations by parenteral administration.

For the express goal of clearing up acne, a tetracycline analogue called sarecycline has been created. We have an oral formulation that can help with moderate to severe non-nodular acne vulgaris, which is characterized by inflammatory lesions. Compared to prior tetracyclines like doxycycline and minocycline, this new tetracycline has a higher level of selectivity against Cutinebacterium acnes, which is the main advantage it offers in treating acne. This specificity reduces the possibility of antibiotic resistance emerging compared to doxycycline and minocycline.

The generations of Tetracyclines. (Rusu A, et al., 2021)

Principal members of the tetracycline class. (Chopra I, et al., 2001)

The third-generation tetracyclines. (Rusu A, et al., 2021)

Is tetracycline a broad spectrum antibiotic?

Yes. In terms of antibiotics, tetracyclines have a number of favorable properties. Some of these benefits include being able to treat infections caused by both Gram-positive and Gram-negative bacteria, being well-tolerated by the body, and being accessible in both oral and intravenous (IV) formulations for the majority of members of this family. The wide spectrum of microorganisms that tetracycline medicines may kill includes spirochetes, obligatory intracellular bacteria, protozoan parasites, and Gram-positive and Gram-negative bacteria. Tetracycline antibiotics are very versatile and widely used in many medical sectors.

References

1. Rusu A, et al., The development of third-generation tetracycline antibiotics and new perspectives, Pharmaceutics, 2021, 13(12): 2085.
2. Grossman T H. Tetracycline antibiotics and resistance, Cold Spring Harbor perspectives in medicine, 2016, 6(4): a025387.
3. Chopra I, et al., Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance, Microbiology and molecular biology reviews, 2001, 65(2): 232-260.