Development and Current Research Status of Commonly Used Antibiotics

In recent decades, thanks to the continuous discovery and development of antibiotics, the incidence and mortality rates of diseases caused by bacterial infections have fallen significantly, earning antibiotics the reputation as one of the greatest advancements in modern medicine. Antibiotics are chemical substances produced by microorganisms (including bacteria, fungi, actinomycetes, etc.) or higher plants and animals during their physiological processes that have the ability to inhibit the activity of pathogens. Later, similar compounds or structurally modified substances produced through chemical or biological means were also included in this category. Therefore, in terms of their origin, currently marketed antibiotics include both natural antibiotics and synthetic antibiotics, such as tetracyclines, macrolides, β-lactams, aminoglycosides, and natural peptide antibiotics.

1. Tetracycline Antibiotics

Tetracycline antibiotics are a class of broad-spectrum antibiotics produced by actinomycetes. Their structural characteristic is the presence of a planar polycyclic structure composed of four hydrocarbon rings within the molecule, hence the name tetracycline. Tetracyclines possess many ideal properties of antibiotic drugs, including the ability to inhibit the activity of pathogens such as Gram-positive and Gram-negative bacteria, proven clinical safety, and acceptable tolerability.

Tetracycline antibiotics have evolved into three generations up to now. The first generation primarily includes natural antibiotics such as chlortetracycline, tetracycline, and oxytetracycline, most of which were isolated from the metabolites of actinomycetes. In 1948, chlorotetracycline was first reported to be extracted from Streptomyces aureus and was subsequently marketed under the name chlortetracycline, with approval for clinical use granted in the same year. Shortly after, researchers at Pfizer also isolated oxytetracycline from Streptomyces fermentation broth, which was approved by the US Food and Drug Administration (FDA) in 1950 and released into the market. In the following two decades, other tetracyclines emerged as natural products produced by Streptomyces or semi-synthetic derivatives, which possessed higher antibacterial efficacy, solubility, and oral bioavailability. For example, metacycline was modified from oxytetracycline, and minocycline was modified from demeclocycline. Tigecycline, a typical third-generation tetracycline, is a semi-synthetic parenteral glycylcycline discovered in 1993 and approved for clinical use by the FDA in 2005. It exerts significant inhibitory effects on extensively drug-resistant Staphylococcus aureus and vancomycin-resistant bacteria, making it the preferred treatment option for severe infections caused by resistant bacteria.

2.Macrolide Antibiotics

Macrolide antibiotics are a class of weakly basic antibacterial agents produced by Streptomyces, characterized by the presence of a macrolide lactone ring as their basic structure, with one or more deoxysugar or aminosugar residues attached to the ring through glycosidic bonds. Macrolides represent a large class of protein synthesis inhibitors and possess extensive clinical value due to their applicability in human medicine. The antibacterial spectrum of macrolide antibiotics includes Mycoplasma, Chlamydia, Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, and others.

The development of macrolide antibiotics has gone through three stages:

① The first generation of macrolide antibiotics, represented by erythromycin, has a 14-membered lactone ring with cladinose sugar and desosamine sugar attached at the C3 and C5 positions, respectively. Modifications to the C4 position of the cladinose sugar can enhance antibacterial activity and broaden the antibacterial spectrum.

② The second generation of macrolide antibiotics, represented by azithromycin, introduces an N atom into the macrolide ring. Compared to erythromycin, second-generation antibiotics improve bioavailability and antibacterial activity. For example, azithromycin exhibits good antibacterial activity against Chlamydia, Mycoplasma, and anaerobic bacteria, and is more active against Haemophilus influenzae and Legionella pneumophila than erythromycin.

③ The most representative of the third-generation antibiotics are the ketolides, such as telithromycin. The introduction of a keto carbonyl group at the C3 position replaces the cladinose sugar in erythromycin, making them insensitive to microbial macrolide resistance mechanisms. The methoxy group at the C6 position enhances their acid stability, while the cyclic carbamate at the C11 and C12 positions further enhances their antibacterial activity.

3.β-Lactam Antibiotics

β-Lactam antibiotics are the most widely used class of antibiotics currently available, characterized by their strong bactericidal capabilities, low toxicity, and good clinical efficacy. They can be effective against diseases caused by both Gram-positive and Gram-negative bacteria. β-Lactam antibiotics all contain a four-membered β-lactam ring, and in most cases, there is also a fused five- or six-membered ring. Based on the differences in the fused ring structure, β-lactam antibiotics are further classified into penicillins, cephalosporins, and atypical β-lactams.

The backbone of penicillin-class antibiotics is a β-lactam fused with a five-membered hydrogenated thiazole ring. Ampicillin, which introduces an amino group at the benzyl position of penicillin, increases its basicity and is the first broad-spectrum penicillin, but it is not resistant to β-lactamases. The introduction of a phenolic hydroxyl group at the 4-position of the phenyl ring of ampicillin yields amoxicillin, which improves oral bioavailability. The main structure of cephalosporins is a β-lactam fused with a six-membered hydrogenated thiazine ring, and they have developed to the fourth generation. Fourth-generation cephalosporins (such as cefpirome) introduce a positively charged quaternary ammonium group at the 3-position, which can form an internal salt with the carboxyl group within the molecule, allowing rapid penetration of bacterial cell walls and binding to penicillin-binding proteins (PBPs). Cefpirome has a 2-aminothiazole-α-methoxyiminoacetyl side chain at the 7-position, and the cis-configuration of the imino group is close to the β-lactam ring, conferring resistance to most β-lactamases and thus exhibiting broad-spectrum antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria. The backbone structure of carbapenems replaces the hydrogenated thiazole ring of the penicillin ring with a dihydropyrrole ring, making them the broadest-spectrum and most potent class of β-lactam antibiotics. The substituent at the 3-position is related to the antibacterial spectrum and antibacterial activity, for example, imipenem has an N-iminomethyl group at the 3-position, while meropenem introduces a pyrrolidine ring at the 3-position, both of which are stable against most β-lactamases. Aztreonam is the first fully synthetic monocyclic β-lactam antibiotic, and the methyl group at the 2-position increases its stability against β-lactamases.

4.Aminoglycoside Antibiotics

Aminoglycoside antibiotics are a class of glycosidic antibiotics formed by the linkage of an aminocyclitol (such as streptamine or 2-deoxystreptamine) and multiple aminosugar molecules through glycosidic bonds. Streptomycin was the second antibiotic produced and used clinically after penicillin, with its derivative aminocyclitol primarily existing in the form of streptamine, while the cyclitols of other aminoglycosides are mostly present as 2-deoxystreptamine (2-DOS). Naturally fermented antibiotics are derived from Streptomyces bacteria (such as streptomycin) and Micromonospora (such as gentamicin). To address the issue of resistance to natural antibiotics and expand the antibacterial spectrum, semi-synthetic antibiotics like amikacin have been developed through structural modification of natural aminoglycosides. Clinically, amikacin is primarily used to treat infections caused by Gram-negative bacteria, particularly urinary tract infections.

Aminoglycoside antibiotics have their glycosidic bonds formed through 4,5-disubstitution or 4,6-disubstitution, and commonly use furanose or pyranose sugars, as well as modified forms of these sugars. Streptomycin is composed of a streptidine linked to a unique five-membered sugar ring, streptose, which is further connected to an N-methylglucosamine via a 1,3-glycosidic bond. Paromomycin has deoxystreptamine as its core, with a glucosamine attached at the 4-position and a disaccharide consisting of ribose-glucosamine at the 5-position. Similarly, amikacin uses deoxystreptamine as its core, with glucosamine disubstituted at the 4,6-positions of deoxystreptamine. Additionally, the amino group at the 3-position is modified by the introduction of a hydroxyl group and an amino group through an amide bond, making it stable against various transferases and less prone to develop resistance.

5.Natural Peptide Antibiotics

Peptide antibiotics are an important class of natural antibiotics primarily produced by bacteria and actinomycetes, encompassing lipopeptides, thiopeptides, and glycopeptides among others. Among these, glycopeptide antibiotics are more widely used in clinical settings. Commonly used glycopeptide antibiotics include vancomycin, norvancomycin, and teicoplanin, which are mostly directly derived from microbial metabolites. To enhance the antibacterial spectrum and half-life of these antibiotics, modifications of natural glycopeptides have led to the development of drugs such as oritavancin, oritavancin, and ramoplanin. Clinically, this class of antibiotics is often used to treat severe infections caused by Gram-positive bacteria, particularly methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus, and they are not degraded by β-lactamases, earning them the title of the "last line of defense" against Gram-positive bacterial infections.

6.Synthetic Antibiotics

Synthetic antibiotics are an indispensable part of the antibiotic family, encompassing sulfa drugs, nitroimidazoles, and quinolones, among others. Quinolone antibiotics are the most widely used in clinical practice due to their potent efficacy and broad antibacterial spectrum. The first-generation quinolones, represented by nalidixic acid, have a relatively narrow antibacterial spectrum and only exhibit inhibitory effects against some Gram-negative bacteria. The second-generation quinolones are primarily represented by flumequine and pipemidic acid. Flumequine was the first quinolone antibiotic to introduce an F atom at the C6 position, while pipemidic acid was the first to incorporate a piperazine group at the C7 position. These modification strategies paved the way for the development of subsequent quinolone antibiotics. In the early 1980s, the development of the first third-generation quinolone antibiotic with a 6-fluoro-7-piperazine structure, norfloxacin, marked a significant milestone, and since then, fluoroquinolones have become the preferred choice for broad-spectrum antibiotics. The fourth-generation quinolones, including levofloxacin, trovafloxacin, moxifloxacin, among others, not only maintain their activity against Gram-negative bacteria but also significantly improve their activity against Gram-positive bacteria. Moxifloxacin, in particular, is known as an "ultra-broad-spectrum antibacterial agent."

References

[1] Feng Kai, Xin Jie, Tian Jun, Chang Honghong, Gao Wenchao. Research Progress on the Structure-Activity Relationship of Natural Antibiotics [J]. Chinese Journal of Antibiotics, 2021, 46(09): 809-820. DOI: 10.13461/j.cnki.cja.007125.

[2] Tang Yuqing, Ye Qian, Zheng Weiyi. Research Status and Progress of Antibiotic Drugs [J]. Foreign Medical Sciences (Antibiotic Section), 2019, 40(04): 295-301. DOI: 10.13461/j.cnki.wna.005229.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.