Amino Acids for Antimicrobial Agents

As the fundamental building blocks of proteins and enzymes in living organisms, amino acids not only participate in various life activities but also play a key role in antimicrobial mechanisms. Amino acids and derivatives have become the subject of a lot of interest in the antimicrobial design and production in recent years. By changing the structure of amino acids, we can construct antimicrobial molecules with more targeted and effective effects. For instance, some amino acids and other synthetic derivatives are the basis of antimicrobial peptides, which are capable of knocking off bacterial cell membranes or blocking bacterial metabolism. Furthermore, amino acids can be conjugated with other medications for antimicrobial activity and reduction of resistance. As science progresses, amino acids have broad potential to find applications in antimicrobial drugs and new avenues for antimicrobial treatment.

What are Antimicrobial Agents?

Since the discovery of penicillin, antimicrobial chemotherapy has been a focal point of medical research. Although hundreds of antimicrobial agents have been discovered, most of them are derived from natural substances or synthetically produced, with less than 1% of them becoming drugs. Among these, bacterial infections are difficult to treat due to the rapid development of resistance and the challenge of bacterial penetration into pathogenic cells. The World Health Organization has prioritized the development of effective antimicrobial drugs, particularly targeting Acinetobacter, Pseudomonas, and carbapenem-resistant Enterobacteriaceae. Fungal infections, especially fatal disseminated fungal diseases in immunocompromised patients, also present significant challenges to modern chemotherapy. The emergence of new fungal resistance and superbugs has limited the variety of antifungal drugs. Antimicrobial agents are chemical substances that can inhibit bacterial growth or kill bacteria. They exert antimicrobial effects by interfering with bacterial metabolic processes, damaging bacterial cell structures, or inhibiting their reproduction. Common antimicrobial agents include antibiotics, antibacterial compounds, and antimicrobial surfactants. Currently, antimicrobial agents are widely used in clinical treatments for bacterial infections and have significant applications in food, agriculture, and environmental management.

Fig. 1. Amino acids for the synthesis of antimicrobial agents (ChemMedChem. 2021, 16(23): 3513-3544).

Antimicrobial Agents Examples

Different types of antimicrobial agents vary greatly in terms of their mechanisms of action, targets, and application scenarios. Below are some examples of common antimicrobial agents, covering various categories of antibiotics, including both natural and synthetic antimicrobial agents, as well as their application fields. Understanding these antimicrobial agents helps to better comprehend their crucial role and broad applications in infection treatment.

Characteristics of Antimicrobial Agents

The characteristics of antimicrobial agents not only include their antimicrobial spectrum, selective toxicity, resistance, pharmacokinetics, and pharmacodynamics, but also their side effects and bacterial resistance mechanisms. These characteristics determine the clinical application and therapeutic effects of antimicrobial agents and highlight the need for scientific and rational management when using antimicrobial agents to ensure optimal efficacy and minimize side effects and the development of resistance.

• Selective Toxicity: Antimicrobial agents exhibit selective toxicity, meaning they can selectively destroy or inhibit bacteria with minimal impact on host cells (such as human cells).
• Pharmacodynamics: The pharmacodynamics of antimicrobial agents show their ability to effectively inhibit or kill bacteria at certain concentrations. The strength of the effect depends on the dosage of the antimicrobial agent, the duration of action, and the bacterial resistance.
• Antimicrobial Spectrum: The antimicrobial spectrum of an antimicrobial agent determines which bacteria it can act upon. Broad-spectrum antimicrobial agents can inhibit a variety of bacteria, while narrow-spectrum agents primarily target specific bacteria.
• Resistance: With the widespread use of antimicrobial agents, bacteria gradually develop resistance. Resistant bacteria show reduced sensitivity to antimicrobial agents, and in some cases, complete failure of the drug, which is one of the major challenges in current antimicrobial drug research.

Antimicrobial Agents Classification

Antimicrobial agents can be classified by their mechanism of action into several types. First, β-lactam antibiotics (such as penicillin and cephalosporins) work by inhibiting bacterial cell wall synthesis, interfering with the cross-linking of the cell wall, and causing bacterial cell rupture and death. Second, antimicrobial agents that inhibit bacterial protein synthesis, such as aminoglycosides (such as gentamicin) and tetracyclines (such as tetracycline), work by binding to bacterial ribosomes, blocking protein synthesis. Aminoglycosides interfere with protein translation, while tetracyclines prevent amino acid transfer and protein chain elongation. Next, fluoroquinolones (such as moxifloxacin) inhibit DNA gyrase or topoisomerase, blocking DNA replication and effectively killing bacteria. Finally, antimicrobial peptides and some antifungal drugs (such as bleomycin) destroy bacterial cell membranes, causing leakage of cellular contents and bacterial death. Antimicrobial agents with different mechanisms of action are applied differently in clinical treatments, and selecting the appropriate antimicrobial agent is crucial for improving treatment outcomes. Additionally, based on their chemical structure, antimicrobial agents can be classified into the following major categories:

• β-Lactam Antibiotics: β-lactam antibiotics, such as penicillin, cephalosporins, carbapenems, and monobactams, work by inhibiting bacterial cell wall synthesis. Their basic structure is the β-lactam ring, which binds to bacterial transpeptidase (also known as β-lactamase) and prevents the cross-linking of the cell wall, leading to bacterial lysis.
• Aminoglycosides: Aminoglycosides, such as gentamicin and streptomycin, contain an amino sugar group and work by binding to bacterial ribosomes, inhibiting bacterial protein synthesis and ultimately causing bacterial death. These antibiotics are particularly effective against Gram-negative bacteria but require caution due to their potential ototoxicity and nephrotoxicity.
• Tetracyclines: Tetracyclines, such as tetracycline and doxycycline, have broad-spectrum antimicrobial activity and inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit of bacteria. Tetracyclines are commonly used to treat a variety of infections, including respiratory, urinary tract, and skin infections.
• Fluoroquinolones: Fluoroquinolones, such as levofloxacin and moxifloxacin, work by inhibiting bacterial DNA gyrase or topoisomerase IV, preventing DNA replication and thereby exerting antimicrobial effects. These drugs have good activity against a wide range of Gram-positive and Gram-negative bacteria and are commonly used for treating complex infections.
• Sulfonamides: Sulfonamides, such as sulfamethoxazole and sulfadiazine, interfere with bacterial folic acid metabolism by inhibiting the enzymes required for folic acid synthesis (such as dihydropteroate synthase). These antibiotics are primarily used to treat respiratory and urinary tract infections.
• Antifungal Drugs: Antifungal drugs, such as fluconazole and itraconazole, usually work by inhibiting sterol synthesis in fungal cell membranes or disrupting their membrane structure. These drugs are mainly used to treat fungal infections, particularly those caused by yeast, mold, and other fungi.
• Antiviral Drugs: Antiviral drugs, such as acyclovir and lopinavir, typically inhibit viral replication, host cell invasion, or interfere with the transmission of genetic information within the virus. Common antiviral drugs are used to treat infections caused by herpes viruses, HIV, influenza, and other viruses.

Chemical Synthesis of Antimicrobial Agents

In the post-antibiotic era, the development of novel antimicrobial agents is urgently needed. Compounds with new molecular targets are particularly important. Although antimicrobial drugs exhibit diverse chemical structures, many of them are antimetabolites, meaning they are structural analogs of microbial metabolic intermediates. The chemical synthesis of antimicrobial agents generally involves isolating and purifying them from natural sources or producing them via total synthesis methods. For example, the synthesis of penicillin starts with the secretion of natural penicillin by the Penicillium fungus, which is then chemically modified to create various derivatives to enhance efficacy or broaden the antimicrobial spectrum. In general, the chemical synthesis of antimicrobial agents can be classified into the following methods:

• Natural Extraction: Extracting natural antimicrobial compounds from microorganisms, plants, or animals, such as penicillin, streptomycin, etc.
• Semisynthesis: Synthesizing new derivatives by chemically modifying natural antimicrobial molecules. For example, semisynthetic cephalosporins are obtained by chemically modifying penicillin.
• Total Synthesis: Fully synthesizing antimicrobial molecules starting from inorganic raw materials. For instance, some aminoglycoside antibiotics are produced via total synthesis.

Amino Acid-based Antimicrobial Agents

The structures of dozens of known antimicrobial agents, antifungals, and antiprotozoal agents are based on amino acid frameworks. In most drugs, the amino acid backbone is crucial to their antimicrobial activity, as it is often a structural analog of the amino acid intermediates in the biosynthetic pathways of various microorganisms. Specifically, some amino acid derivatives, such as amino phosphonates or amino boronates, are effective enzyme inhibitors because they mimic the tetrahedral transition state intermediates. Based on this, BOC Sciences is dedicated to providing a wide range of natural and non-natural amino acid derivatives to support the synthesis and development of amino acid-based antimicrobial agents.

How Antimicrobial Agents Work?

The mechanism of action of antimicrobial agents primarily relies on interfering with the essential physiological processes of microorganisms, including cell wall synthesis, protein synthesis, nucleic acid synthesis, and cell membrane function. Different types of antimicrobial agents exert their effects through different mechanisms. Below are the principles of action for common antimicrobial agents:

• Disrupting Bacterial Cell Walls

Antimicrobial agents that inhibit bacterial cell wall synthesis are among the most common, especially β-lactam antibiotics (such as penicillin, cephalosporins, etc.). The bacterial cell wall is a protective structure essential for maintaining cell shape and resisting environmental pressures. β-lactam antibiotics work by binding to transpeptidases involved in bacterial cell wall synthesis, thereby inhibiting the synthesis of peptidoglycan. This weakens the bacterial cell wall, ultimately causing cell rupture and death. Since human cells lack cell walls, these antibiotics have minimal effects on human cells, thus exhibiting high selectivity.

• Interfering with Protein Synthesis

Many antimicrobial agents work by inhibiting protein synthesis in bacteria. Aminoglycosides (such as gentamicin, streptomycin) and tetracyclines (such as tetracycline, doxycycline) are representative examples. Aminoglycosides bind to the 30S subunit of the bacterial ribosome, blocking the translation phase of protein synthesis, preventing bacteria from producing essential proteins, which either inhibits their growth or directly kills the bacteria. Tetracyclines work by binding to the 30S subunit of the ribosome, preventing the transfer of amino acids and thereby inhibiting protein synthesis. Since proteins are essential for bacterial life, the action of these antimicrobial agents directly affects bacterial growth and reproduction.

• Inhibiting Nucleic Acid Synthesis

Fluoroquinolone antibiotics (such as levofloxacin, moxifloxacin) exert their antimicrobial effects by inhibiting bacterial DNA replication and repair. These drugs bind to bacterial DNA gyrase and topoisomerase, preventing their normal DNA unwinding and repair functions. This inhibits bacterial DNA replication and transcription, ultimately preventing the bacteria from reproducing.

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