Broad Spectrum and Narrow Spectrum Antibiotics

In recent decades, due to the continuous discovery and development of antibiotics, the incidence and mortality of diseases caused by bacterial infections have dropped dramatically, and antibiotics have been hailed as one of the greatest advances in modern medicine. Antibiotics are chemical substances produced by microorganisms (including bacteria, fungi, actinomyces, etc.) or higher animals and plants in the physiological process that have the activity of inhibiting pathogens, and later people have also classified similar compounds or structural modifications prepared by chemical or biological means. Therefore, the current classification of antibiotics includes synthetic compounds as well as those produced by natural microorganisms. Of course, as the range of antibiotics continues to increase, how to classify and distinguish these compounds has been a topic of discussion. At present, the generally accepted and used categories are: mode of action, molecular structure, and spectrum of activity.

Classification of antibiotic

Mode of action

According to the different ways in which antibiotics inhibit/kill bacteria, the following four modes of action can be listed: A. Inhibit cell membrane synthesis. B. Inhibit protein biosynthesis. C. Affect DNA replication and transcription. D. Inhibition of bacterial growth In which antibiotics are divided into antibacterial and bactericidal agents (bacteriostatic) and bactericidal agents (bactericidal). As expressed literally, bacteriostatic can only limit bacterial growth and development, and bifungicides can fundamentally destroy bacteria.

Molecular structure

Compared with the other two classification methods, molecular structure is the only method that can completely distinguish the types of antibiotics. By 1995, more than 10,000 antibiotics had been fully structurally analyzed. According to the chemical agency, the physical properties, chemical properties and toxicity of the antibiotic will be fully identified. In the synthetic step, even minor structural changes can lead to radical changes in antibiotic properties and even effects.

Spectrum of activity

According to the ability to produce effective inhibition against different bacterial species, antibiotics can be roughly divided into narrow spectrum antibiotics and broad spectrum antibiotics. antibacterial spectrum refers to the class, genus, and species range of microorganisms that can be inhibited (or killed) by one or a class of antibacterial drugs, including broad/extended spectrum and narrow spectrum. For example, the antibacterial spectrum of penicillin mainly includes gram-positive bacteria and some negative bacteria, and the antibacterial spectrum of streptomycin is mainly some Gram-negative bacteria, and the coverage of the antibacterial spectrum of both is narrow, so it is a narrow spectrum antibiotic. The antibacterial spectrum of tetracycline includes gram-positive bacteria and gram-negative bacteria, chlamydia, mycoplasma, rickettsia, spirochaeta, amoeba, and is a broad-spectrum antibiotic.

For clinical purposes, although broad-spectrum antibiotics have received more attention, it does not mean that either class of antibiotics is better. When choosing antibiotics, more attention should be paid to the corresponding targeted bacteria, rather than blindly choosing broad-spectrum antibiotics. Long-term use or misuse of Antibiotics can lead to the development of Antibiotics resistant gene in the body. This gene can spread throughout the bacterial population and between different bacterial species, which can eventually cause drugs to fail and produce more severe and deadly results.

What are broad spectrum antibiotics?

Broad-spectrum antibiotics are a class of antibiotics that can inhibit or kill many types of bacteria. The main advantage of this class of antibiotics is that they can work against both gram-positive and Gram-negative bacteria, and are not limited to specific pathogens. This property makes broad-spectrum antibiotics useful in situations where the source of the infection is uncertain or where multiple pathogens are involved. Common broad spectrum antibiotics include ampicillin, cephalosporins and quinolones.

Advantages of broad spectrum antibiotics

Versatility in treatment: Broad-spectrum antibiotics are invaluable in situations where the causative bacteria are unknown. Their ability to target a wide range of pathogens makes them particularly useful in emergency settings or when immediate treatment is required.

Polymicrobial infections: These antibiotics are often the first line of defense against polymicrobial infections, where multiple types of bacteria are involved. Their broad action can address complex infections, such as those arising from surgical wounds or abscesses.

Reduction in time to effective therapy: In cases of severe illness, such as sepsis, initiating treatment with broad-spectrum antibiotics can significantly reduce the time to effective therapy, potentially improving patient outcomes and survival rates.

Disadvantages of broad spectrum antibiotics

Disruption of normal microbiome: One of the significant drawbacks of broad-spectrum antibiotics is their impact on the body's normal flora. By indiscriminately killing both pathogenic and beneficial bacteria, these agents can lead to dysbiosis, which can result in opportunistic infections, such as Clostridioides difficile colitis.

Increased risk of resistance: The widespread use of broad-spectrum antibiotics contributes to the development of antimicrobial resistance. This can render certain bacteria more virulent and harder to treat, posing a significant public health challenge.

Adverse effects: Patients may experience a range of side effects, from gastrointestinal disturbances to allergic reactions. The broad nature of these antibiotics can also lead to complications associated with the eradication of beneficial microorganisms.

Limited efficacy against resistant strains: While broad-spectrum antibiotics can address a wide variety of infections, they may not be effective against resistant strains, necessitating further testing and potential use of more potent, narrow-spectrum alternatives.

Examples of broad spectrum antibiotics

Tetracycline(except sarecycline): Tetracycline antibiotics are a class of broad-spectrum antibiotics produced by actinomycetes, whose structure is characterized by a planar polycyclic structure composed of 4 hydrocarbon rings within the molecule, so the name tetracycline. Tetracycline has many desirable properties of antibiotic drugs, including activity against pathogens such as gram-positive and gram-negative bacteria, proven clinical safety, and acceptable tolerability. Tetracycline antibiotics have been developed for 3 generations.

Quinolone: Quinolone antibiotic is widely used in clinic because of its high efficacy activity and wide antibacterial spectrum. Nalidixic acid is the main antibacterial spectrum of the first generation quinolone antibiotics, which only has a certain inhibitory effect on some gram-negative bacteria. The second generation is dominated by flumequine and piperidinic acid. The former is the first quinolone antibiotic to introduce F atom at C6 position, and the latter is the first drug to introduce piperazine group at C7 position. These two modification strategies provide new ideas for the development of subsequent quinolone antibiotics. In the early 1980s, norfloxacin, the first third-generation quinolone antibiotic with 6-fluoro-7-piperazine structure, was developed, and its emergence was epoch-making, since then fluoroquinolones have become the preferred broad-spectrum antibiotics. The fourth-generation quinolone antibiotics include levofloxacin, trevafloxacin, moxifloxacin, etc., while maintaining the activity against gram-negative bacteria, the activity against gram-positive bacteria is also greatly improved, of which moxifloxacin is known as "ultra-broad spectrum antibacterial drugs".

Ampicillin: Ampicillin introduces an amino group at the benzyl of penicillin to increase its alkalinity; it was the first broad-spectrum penicillin, but was not resistant to beta-lactamase. Amoxicillin can be obtained by introducing phenol hydroxyl at the 4 position of ampicillin, which can improve oral availability.

Cephalosporin: The main structure of cephalosporins is β-lactam and six-membered hydrothiazine ring, which has been developed to the fourth generation. The fourth generation of cephalosporins (such as cefpirome) introduce positively charged quaternary ammonium groups at position 3, which can quickly penetrate the bacterial cell wall to form internal salts with carboxyl groups and bind to penicillin-binding proteins (PBPs). The 7-position side chain of Cefpirol is 2-aminothiazole-α-methyloxyimidoacetyl, the cis-structure of the imidogroup is close to that of the β-lactam ring, and it is resistant to most β-lacamases, so it shows broad-spectrum antibacterial activity against gram-positive bacteria, gram-negative bacteria, and anaerobic bacteria.

Broad spectrum antibiotics at BOC Sciences

What are narrow spectrum antibiotics?

Narrow-spectrum antibiotics are specifically designed to target a limited range of bacteria, either Gram-positive or Gram-negative. Their specificity allows for effective treatment with minimal impact on the normal microbiota.

Narrow spectrum antibiotics examples

Fidaxomicin: Fidaxomicin (Fdx), also known as tiacumicin, is a class of macrolide antibiotics widely used in the treatment of Clostridium difficile (Cdiff) infections. Cdiff is a toxin-producing Gram-positive gut bacterium that is resistant to a variety of antibiotics. The main symptom of Cdiff infection is to cause fatal diarrhea, which is the main pathogen of hospital infection resulting in death, and is listed as an "emergency threat" microorganism by the U.S. Center for Disease Control and Prevention. Broad-spectrum antibiotics such as vancomycin, metanidazole and other drugs have been used to treat Cdiff infection, but because broad-spectrum antibiotics are not selective to bacteria, they inhibit the growth of clostridium difficile while killing most of the symbiotic microorganisms in the gut, but make the infection caused by clostridium difficile easy to relapse after stopping the drug. In 2011, Fdx, a narrow-spectrum antibiotic for the treatment of Cdiff infection, was successfully marketed as a drug that selectively inhibits the growth of Cdiff in the gut flora.

The narrow spectrum antibiotic Fdx selectively inhibits Cdiff. (Cao, X., 2022)

Sarecycline: A newer antibiotic effective against specific strains of acne-causing bacteria, minimizing disruption to skin flora.

Narrow spectrum antibiotics at BOC Sciences

Antibiotic production services at BOC Sciences

Differences between broad and narrow spectrum antibiotics

The size of the normal flora affected by antibiotics is related to the antibacterial spectrum of the antibiotics selected, that is, it is related to the broad and narrow antibacterial spectrum. Narrow-spectrum antibiotics are only active against one or a few bacteria, broad-spectrum antibiotics can be active against two or more bacteria, and ultra-broad-spectrum antibiotics are active against many or most bacteria. The wider the antibacterial spectrum of an antibiotic, the wider the spectrum of bacteria affected, and the more normal flora that is killed or inhibited.

In general, narrow-spectrum antibiotics are highly targeted and not prone to double infections, but in the treatment of severe or mixed multiple bacterial infections, a combination of drugs is needed. However, broad-spectrum antibiotics have wide antibacterial spectrum and wide application range, which are easy to produce drug resistance and double infection, and their pertinency is not as strong as narrow-spectrum antibiotics. So both broad-spectrum and narrow-spectrum antibiotics have advantages and disadvantages.

Researchers at the University of Illinois and Harvard University report in Nature that they have developed a platform for framing fully synthetic analogues of a family of lincoamines, identifying a class of broad-spectrum antibiotics that overcome multidrug resistance in bacteria. Guided by the X-ray crystal structure of lincoamines bound to the ribosome, and taking advantage of the modularity of these molecules, the researchers developed the so-called "hemispheres," the corresponding amino acid and amino sugar components. Using these components, researchers can make electrically subversive changes to the molecular structure. By aminating these hemispherical components, the researchers assembled more than 500 lincoamine analogues.

Testing the antibacterial activity of these analogs showed that embedding 7-atom rings into the amino acid hemispheres significantly improved the antibacterial efficacy and range of synthetic antibiotics, with the analogue known as iboxamycin showing exceptional performance. This work highlights that synthetic chemistry is an important weapon in the fight against bacterial resistance. The antibiotic led by iboxamycin synthesized by the institute not only can effectively resist bacterial resistance, but also shows a broad spectrum of antibacterial activity, and has achieved remarkable therapeutic effect in animal experiments.

References

1. Cao, X., et al. Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile. Nature. 2022, 604(7906): 541-545.
2. Mitcheltree, M.J., et al. A synthetic antibiotic class overcoming bacterial multidrug resistance. Nature. 2021: 599, 507-512.