See also Antibiotic Resistance Mechanisms

In order to successfully colonize the gut and cause infection or disease, bacteria (or pathogenic bacteria) have evolved multiple virulence factors in interaction with the human microbiome that enable them to counteract colonization resistance.

Mobility and chemotaxis:

Flagellar motility and chemotaxis help bacteria to find sources of nutrients and localize suitable ecological niches for growth, improving the efficiency of bacterial environmental colonization. Falgellar mediated chemotaxis can assist bacteria to reach specific sites in new hosts, facilitating its colonization or invasion as well as growth and maintenance. (Yu, “The spread of antibiotic resistance to humans and potential protection strategies” Ecotoxicology and Environmental Safety 254 (2023).

Some studies have reported that essential oils and ethanolic extracts have been confirmed to reduce the invasion of Campylobacter jejuni on INT407 epithelial cells and motility through modulation of its LuxS system. Flagellar motility and its medaited chemotaxis are essential for bacterial colinization and thus the reduction of the flagellar motility of bacteria could b e a target for anti-colonization. (Yu, “The spread of antibiotic resistance to humans and potential protection strategies” Ecotoxicology and Environmental Safety 254 (2023)

Adhesion and invasion:

Adhesion and invasion are key steps in the colonization and infection of bacteria within the host. This procss requires the help of functional adhesins such as fibronectin-binding and laminin-binding proteins (Lmb). Fibronectin-binding proteins A and B is also important for persistent colonization of Staphylococcus aureus in the nose and intestine. Pili, especially tpe IV pili also play an important role in bacterial adhesion, ecological niche selction and establishment. Disruption of bacterial pilus-mediated adhesion processes can be achieved through inhibition of bacterail pilus production, adhesion inhibition, and adhesion based vaccines and antibodies. (Yu, “The spread of antibiotic resistance to humans and potential protection strategies” Ecotoxicology and Environmental Safety 254 (2023)

Type VI Section System:

The type VI secretion system (T6SS) is used in gram-negative bacteria and can deliver toxic substances to competitors and kill them or alter some of their key funcitons, which provides an advantage for the apthogen to conquer the colonization resistance of the host commensal bacterail. This promotes its colonizaiton and persistence. Effective inhibition of T6SS can reduce the invasion of commensal microbiome and niche dominance by exogenous pathogens. A mixture of organic acids and plant extracts was reproted to down-regulate the expression of T6SS related genes and reduce the virulence and cecum colonization of Camplobacter jenuni and Camplylobacter coli. (Yu, “The spread of antibiotic resistance to humans and potential protection strategies” Ecotoxicology and Environmental Safety 254 (2023)

Disruption of Human Gut Microbiome:

The human gut microbiome is well known to be an improtant reservoir of ARG and likely to be a key factor in regualting the emergency and spread of ARB. Antibiotic therapy for example can have a large impact on the human gut microbiome and its resistome, which eliminates not only pathogenic but also beneficial bacterial. The impact of antibiotics is influenced by the tyep of antibiotic, the route of adminsitration and the microbiome status of the patient. Antibiotics, expecially broad spectrum antibiotics, may generally have a negative impact on the diversity of the gut microbiome and promote the expansion of antibiotic specific ARG in humans. Appropritate routes of adminsitraiton combined with antibiotics with less impact on the gut microbiome can better reduce antibotic resistance while minimizing damage to the gut microbiome. (Yu, “The spread of antibiotic resistance to humans and potential protection strategies” Ecotoxicology and Environmental Safety 254 (2023)

Fecal microbiota transplantation (FMT), the delivery of feces form a healthy donor to the recipient’s intestine via enema or oral capsule, can rapidly reverse diseases assocaited with intestinal flora dysbiosis, enhance Cr, and limit increasing antibiotic resistance. FMT is theoretically the replacement of ARB in the recipient by a high abundance of non-antibiotic resistant bacteria.

Probiotics and prebiotic regulate the intestinal microbiota to enhance its CR intestinal barrier function. Some probiotic organisms (like lactobacillus rhamnosus GG, Lactobacillus casei Shirota, Bifidobacterium animalis Bb-12 and Saccharomyces crevisia boulardii have been reported to enhance nonspecific cellular immune response and miantain the gut homeostasis.

A healthy gut microbiome is critical for maintaining its CR and reducing exogenous bacterial colonization. Dietary fiber can promote the production of SCFA (including acetate, propionic acid and butyric acid) by relevant bacterial. SCFA plays an important role in maintaining the integrity of the gastrointestinal barrier and the loss of SCFA may lead to a decrease of CR against pathogenic bacteria. For instance, in patients receiving antimicrobila therpay, the abundance of the SCFA producing commensal bacteria decrased, accompanied by the expansion of carbopenem-resistant Enterobacteriaceae . SCFA inhibited the growth of antibiotic-restant E. coli and K. pneumoniae. Conversely, a high sugar, high fat, and high protein diet promoted colonizaiton by exogenous bacteria and promoted ARG expansion and transfer. (Yu, “The spread of antibiotic resistance to humans and potential protection strategies” Ecotoxicology and Environmental Safety 254 (2023)

Polyphenols like pomegranate ellagitannins, green tea polyphenols, rsveratrol, juice, blueberry and mango pup polyphenols and vitamins (A dn D) and Omega-3 fatty acids, also play an essential role in regualting microbiota and strenghtening barrier funciton. Polyphenols expand the population of beneficial species such as Bifidobacterium and Lactobacillus. and significantly enhance intesting related bacterial produciton of SCFA, which enhance intestinal barrier funciton.

Urease:

Urease is a virulence factor found in various pathogenic bacteria. It is essential in colonization of a host organism and in maintenance of bacterial cells in tissues. Due to its enzymatic activity, urease has a toxic effect on human cells. Urease is also an immunogenic protein and is recognized by antibodies present in human sera. The presence of such antibodies is connected with progress of several long-lasting diseases, like rheumatoid arthritis, atherosclerosis or urinary tract infections. (Kaca “Bacterial Urease and its Role in Long-Lasting Human Diseases” Current Protein and Peptide Science, 2012, 13, 789-806).

Ureolytic activity is often observed in pathogenic bacteria. Such a feature is characteristic of pathogenic Staphylococcus strains. Over 90% of clinical methicillin resistant Staphylococcus aureus strains are capable of urea hydrolysis. (Kaka “Bacterial urease and its role in long-lasting human diseases, Current protein Peptide Science, 2012).

In bacterial ureases, motives with a sequence and/or structure similar to human proteins may occur. This phenomenon, known as molecular mimicry, leads to the appearance of autoantibodies, which take part in host molecules destruction. Detection of antibodies-binding motives (epitopes) in bacterial proteins is a complex process. However, organic chemistry tools, such as synthetic peptide libraries, are helpful in both, epitope mapping as well as in serologic investigations. (Kaka “Bacterial urease and its role in long-lasting human diseases, Current protein Peptide Science, 2012).

Urease is capable of urea hydrolysis. This compound is widespread: it is found in the natural environment (water and soil) and in human body, where its occurrence is connected with protein degradation. In humans, urea is a factor of normal functions of kidneys. (Kaka “Bacterial urease and its role in long-lasting human diseases, Current protein Peptide Science, 2012).

A healthy adult excretes about 30 g of urea per day. However, it is present not only in urine, but also in blood serum, sweat and even in stomach.

Urease is a nickel-containing enzyme, which requires activity of a few additional proteins for acquisition of its hydrolytic properties. This process involves genes coding structural enzyme polypeptides as well as genes coding accessory proteins, located in a joint cluster.

The role of urease in bacterium surviving in unfavorable microenvironment in the host’s body is especially noticeable in case of H. pylori, a causative agent of gastritis and peptic ulceration. Ureolytic activity is essential for surviving M. tuberculosis, an etiologic factor of tuberculosis, a long-lasting inflammatory lung disease. Bacteria infect macrophages. They reside in phagosome, where alkalization due to ureolytic activity and subvert phagosome maturation takes place. Additionally, urease activity enables bacterium to exist in the environment where nitrogen sources are limited to urea.