Antibiotic Resistance: Definition, Mechanism and Source
What is antibiotic resistance?
Antibiotic resistance refers to the ability of microorganisms (such as bacteria, fungi, etc.) to resist one or more antibiotic drugs that are effective, causing these drugs to be less effective or completely ineffective against these microorganisms.
Antibiotic resistance has become a major danger to humanity, causing an estimated 700,000 deaths worldwide each year, and it is predicted that millions more will die by 2050 if the problem is not adequately addressed. Antibiotic resistance is a global health emergency, with resistance found in all antimicrobials currently in clinical use, but only a handful of new drugs in the pipeline. Understanding the molecular mechanisms underlying bacterial resistance to antimicrobial action is critical for identifying global patterns of resistance and improving the use of existing drugs, as well as designing new drugs that are less susceptible to resistance and new strategies to combat it.
Molecular mechanism of microbial resistance to antibiotics
Bacteria have a variety of antibiotic resistance mechanisms, which are roughly divided into two categories: inherent resistance and acquired resistance. Inherent drug resistance refers to the resistance genes carried by bacteria in order to survive in the environment exposed to antibiotics. Acquired resistance means that bacteria acquire new genetic material from the outside world to become resistant to antibacterial drugs. The molecular mechanism of antimicrobial resistance mainly includes: (1) decreased permeability; (2) active efflux of antibiotics; (3) change, modification and protection of target protein; (4) drug inactivation and modification; (5) target bypass.
Decreased permeability
Many antimicrobials need to enter the cell to exert their antibacterial activity, so the change of pore protein structure is also an important factor affecting antimicrobial resistance. Porins in the outer cell membrane are divided into the following categories based on function and structure: non-specific channels (e.g. OmpF and OmpC); Substrate specific channels (e.g. PhoE and LamB); Beta - bucket channels (e.g. OmpA and OmpX). Normally, porins allow < 600kDa hydrophilic compounds to enter the cell. However, different porin structures allow different drugs to pass through; for example, the pore size of OmpF is larger than that of OmpC, and drugs can pass through the OmpF channel more easily. Carbapenem resistance in Klebsiella pneumoniae was partly mediated by modifications of non-selective porins OmpK35 and OmpK36. (Gly115-Asp116) Selective insertion into loop3 of OmpK36 results in significant pore shrinkage, thereby increasing tolerance to carbapenems. Multiple mutations in multidrug-resistant Escherichia coli OmpC alter the charge in pores and thus affect the permeability of antibacterial agents such as cefotaxime, gentamicin, or imipenem. The expression of porin in enterobacter is influenced by environmental stimuli, and the expression of OmpC and OmpF in Escherichia coli is controlled by the ENVZ-OMPR two-component system. EnvZ is a periplasmic sensor protein that senses environmental changes and controls the phosphorylation of its homologous response regulator, OmpR. High levels of phosphorylated OmpR in cells lead to decreased ompF and increased ompC transcription. This differential regulation of the two porins allows for appropriate porin expression: in nutrient-rich environments with high osmotic pressure, pores dominate. Mutants that produced only smaller pores survived better in an antibacterial exposure environment.
Active transport of antibiotics
Bacteria can also actively excrete drugs through efflux pumps to form resistance. Efflux pumps are transmembrane proteins that transport antibiotics to bacterial membranes in an energy-dependent manner, working in synergy with an impermeable double-membrane structure that makes some pathogens inherently resistant to many antimicrobial agents. There are six families of effervescent transporters, among which the resistance-Nodulation division (RND) family has a very large range of substrates and is the effervescent transporter most associated with clinical drug resistance level in Gram-negative bacteria, including Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae and Bacillus baumannii. Overexpression of efflux pumps can cause multidrug resistance (MDR) in clinical isolates. Therefore, clarifying the structure, function, and regulatory mechanisms of efflux pumps provides a clear opportunity to restore drug sensitivity.
Alteration, modification and protection of target proteins
Antibacterial agents bind the main target proteins in bacteria with high affinity, inhibit the basic cell function of bacteria and thus inhibit their growth or cause their death. If the structure of the target protein is changed or protected by modification with other chemical components, it will reduce the efficiency of binding to antibiotics, resulting in resistance.
Target protein change: The change of target protein can be caused by the accumulation of random point mutations of target genes during bacterial growth. The mutant alleles of target genes can also be produced with high frequency through gene recombination between alleles. Alternatively, through transformation, replacement alleles are obtained from related species and Mosaic genes are produced through recombination.
Target protein modification: Modification of drug target proteins can also lead to drug resistance, such as the methylation of 16S rRNA by ribosome methyltransferase, which prevents the binding of macrolides, leading to the formation of resistance.
Formation of target protection proteins: The formation of target protection proteins can inhibit the action of antibacterial drugs, such as binding to the drug target protein and removing the drug from the target protein; The target protection protein can bind to the drug target protein and mediate the allosteric dissociation between the drug and the target protein. Target protection proteins can bind to drug target proteins and cause conformational changes that allow the target proteins to function even in the presence of the drug.
Modification and inactivation of antimicrobial agents
The modification and deactivation of antibacterial agents are mediated by various modifying enzymes and hydrolases, which can hydrolyze functional groups of agents and destroy their antibacterial activities. Modifying enzymes (such as acetyltransferase, methyltransferase, or phosphotransferase) can modify an antibiotic by covalent transfer of various chemical groups to prevent it from binding to the target protein.
Target bypass
Target bypass is a strategy to replace the original target protein by another alternative pathway. Take the formation of methicillin-resistant Staphylococcus aureus (MRSA) as an example. Beta-lactam antibiotics, such as methicillin, bind to PBP and inhibit the transpeptidase domain, leading to disruption of cell wall synthesis. Staphylococcus aureus can acquire exogenous PBP (PBP2a) that is homologous to the original target but has a low affinity for beta-lactam drugs. The protein is encoded by the mecA gene (methicillin-resistant gene), which is located in the Staphylococcal cassette chromosome mec (SCCmec), a mobile genetic element that confers methicillin resistance. When methicillin binds to this alternative target, inhibition of cell wall synthesis is prevented because the transpeptidase activity of PBP2a remains unchanged. With this mechanism, Staphylococcus aureus can bypass the effects of methicillin to ensure cell survival.
What causes antibiotic resistance?
Genetic variation in bacteria: Bacteria develop drug resistance through genetic or chromosomal mutations. For example, certain bacteria can resist the effects of antibiotics by altering their gene expression. This genetic mutation can be a simple point mutation or a more complex genomic change such as insertion or deletion.
Misuse of antibiotics: The widespread use and misuse of antibiotics is one of the main reasons for the rapid spread of drug resistance. When bacteria are exposed to antibiotics, those with resistance genes survive and multiply, increasing the spread of resistance.
Antibiotics in wastewater: Human use of antibiotics leads to a large number of drug-resistant bacteria and their resistance genes in medical wastewater and domestic sewage, especially medical wastewater is considered to be a rich integron gene pool. Therefore, centralized treatment in urban sewage treatment plants has become an important source of the spread of antibiotic-resistant bacteria and resistance genes. Studies have shown that there are high abundance and extremely diverse resistance genes in influent, effluent and sludge from sewage treatment plants, and effluent from sewage treatment plants can significantly increase the resistance level in the receiving water environment.
Aquaculture use: The discharge of organic waste and sewage from intensive farming systems (including aquaculture) releases a large number of resistance factors directly into the environment. What is more serious is that the environmental management of the aquaculture industry is relatively extensive, and the relatively low waste disposal and recycling technology further aggravates the pollution. Studies have shown that the overuse of antibiotics and heavy metal additives in intensive farming can enrich resistance genes (genes that cause microorganisms to develop antibiotic resistance) in pig manure up to 10,000 times higher than the background value.
Misuse in manufacturing facilities: Waste water and residue discharge from antibiotic pharmaceutical enterprises. The waste of antibiotic pharmaceutical enterprises contains high concentration of antibiotic residues, and long-term selection pressure can lead to it becoming a rich reservoir of resistance genes.
Antibiotic production services at BOC Sciences
Antibiotic resistance stewardship
Strengthen supervision: Formulate relevant laws, regulations, policies and measures to regulate the production, sale and use of antibiotics. At the same time, the supervision of medical institutions and doctors should be strengthened to ensure that they use antibiotics in accordance with the principle of rational drug use.
Rational drug use: Ensure that the correct antibiotic, dose, duration of treatment, and route of administration are selected to maximize the efficacy of clinical cure or prevention of infection, while limiting the side effects of antibiotic use such as toxicity, selective pathogens (such as Clostridium difficile), and the emergence of resistance.
Developing new antibiotics: Microbes still possess many natural antimicrobials that scientists have yet to exploit. For example, researchers testing actinomycetes compounds used to look for broad-spectrum antibiotics, and so may have missed molecules with a narrower target range. Artificial intelligence can be used to screen antimicrobial drugs.
Alternative technology application: An alternative to traditional approaches to drug development is to influence pathogenicity by targeting specific virulence factors involved in the process, a strategy that aims to prevent bacteria from developing resistance and thus control its spread. Molecules that interfere with virulence factors will disarm the pathogen, thus allowing the bacteria to be cleared by the host's immune system.
Effective diagnosis: Quickly and accurately diagnosing the causes of infections and identifying the antibiotics that are sensitive to them can reduce antibiotic use and slow the evolution of resistance.
Strengthen international cooperation: Antibiotic resistance is a global problem that requires a global response. Countries should strengthen international cooperation to jointly study the generation mechanism of antibiotic resistance and response strategies. At the same time, information sharing and technology exchange should be strengthened to promote cooperation and exchanges among countries in the field of antibiotic resistance.
Reference
- Darby, E. M., et al. Molecular mechanisms of antibiotic resistance revisited. Nature Reviews Microbiology. 2023, 21(5): 280-295.
