Mechanisms of resistance of Gram-negative bacilli to antibiotics
Bacteria belonging to the order Enterobacterales constitute a large, closely related group of Gram-negative bacilli. These include, among others: Escherichia coli, Klebsiella pneumoniae and Salmonella spp. Many bacteria belonging to this order constitute the intestinal flora of healthy people. Some species are obligate pathogens. Due to their close relationship, these microorganisms show a number of similarities. One of them is the ability to produce beta-lactamases, enzymes that destabilize the β-lactam bond in the molecule of β-lactam antibiotics. These antibiotics include: penicillins, cephalosporins, carbapenems and monobactams.
History of antibiotics
The discovery of the bactericidal properties of penicillin by Alexander Fleming in 1928 marked the beginning of a new era in medicine. This first antibiotic was introduced to pharmacies in 1946. Even before its introduction to the market, there were reports of Escherichia coli strains capable of producing penicillinase that inactivates this antibiotic. The phenomenon of the spread of penicillin resistance mechanisms was documented very early also in Staphylococcus aureus, and then in other bacterial species. Initially, antibiotic-resistant strains were detected only in hospital patients. Soon, however, antibiotic-resistant bacteria also appeared outside hospitals. The years 1940-1960 are called the golden era of antibiotics. During this period, further antibiotics were introduced, and their wide selection allowed for bypassing resistance mechanisms and effective therapy. The introduction of new generations of penicillins and other antibiotics went hand in hand with the development of resistance among bacterial cells. Since the discovery of penicillin, over 150 antibiotics have been found, and most of them have developed resistance mechanisms
Reasons for the development of antibiotic resistance in bacteria
Bacterial resistance to antibiotics allows bacteria, yeasts and molds to survive in their environment. These substances are produced by them as defense mechanisms. They allow competition for space and food resources with other microorganisms in the environment. The mechanisms that determine bacterial resistance to antibiotics arise primarily as a result of spontaneous mutations and the acquisition of genetic information as a result of horizontal gene transfer (HGT). The genes responsible for resistance are favored in the process of natural selection.
The wide use of antibiotics in medicine, agriculture and animal breeding results in the selection of resistant strains. This includes the use of prescription drugs to combat diseases that do not require the use of this group of drugs. An example is the administration of antibiotics in the case of colds or flu, i.e. viral infections. In recent years, attention has been paid to the particular importance of the overuse of antibiotics in agriculture and animal husbandry. It is estimated that approximately 80% of antibiotics in the United States are sold to control infections, promote growth, and increase weight gain in farm animals. These substances are called antibiotic growth promoters (ASW). However, these substances belong to the same groups of chemical compounds as antibiotics used in medicine. Therefore, such a widespread use of ASW has significantly contributed to the development of antibiotic resistance of bacteria, including those pathogenic to humans. The spread of resistant strains is greatly influenced by environmental contamination with antibiotic growth promoters that enter the ecosystem along with the excretions of farmed animals.
Extended substrate spectrum β-lactamases (ESBL)
One of the most significant mechanisms of antibiotic resistance in Enterobacterales is the production of enzymes capable of hydrolysis: penicillins, cephalosporins and monobactams. These enzymes are called extended-spectrum β-actamases (ESBLs). The mechanism was detected in 1983 in Klebsiella pneumoniae. Initially, ESBL bacteria were known only as etiological factors of hospital infections. Currently, they are also detected as a source of community-acquired infections, and cases of carriers of these bacteria are also known.
New Delhi metallo-β-lactamase (NDM-1)
The mechanism was first diagnosed in 2008 in Klebsiella pneumoniae and Escherichia coli. Its name comes from the city where the patient from whom the first NDM-1 positive bacteria were isolated was staying. The described mechanism involves the production of an enzyme from the group of metallo-β-lactamases. It confers resistance to bacteria to many beta-lactam antibiotics, including carbapenems. Carbapenem antibiotics are considered drugs of last resort. Mainly used to treat diseases caused by bacteria resistant to other antibiotics. Substances from this group are particularly important due to their wide spectrum of action. Carbapenems are active against aerobic and anaerobic pathogenic bacteria, both Gram-positive and Gram-negative.
Undiagnosed resistance of pathogens to a number of antibiotics is often the cause of long-term and ineffectively treated infections. They are often very dangerous and can lead to complications and even death of the infected person.