Journal of Preventive, Diagnostic and Treatment Strategies in Medicine

: 2022  |  Volume : 1  |  Issue : 1  |  Page : 30--34

Cystic fibrosis: Mutations, modulators and microbiology

Pippa J Blevings1, John E Moore2, Beverley Cherie Millar2,  
1 School of Medicine, Dentistry and Biomedical Sciences, The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, Northern Ireland, United Kingdom
2 School of Medicine, Dentistry and Biomedical Sciences, The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University; Laboratory for Disinfection and Pathogen Elimination Studies, Northern Ireland Public Health Laboratory, Belfast City Hospital; Northern Ireland Regional Adult Cystic Fibrosis Centre, Level 8, Belfast City Hospital, Belfast, Northern Ireland, United Kingdom

Correspondence Address:
Beverley Cherie Millar
Northern Ireland Public Health Laboratory, Belfast City Hospital, BT9 7AD, Belfast, Northern Ireland
United Kingdom


The last decade has witnessed an unprecedented arrival and introduction of several new innovations in the treatment and management of cystic fibrosis (CF), all for the benefit of people with CF (PwCF). Such innovations have been largely led by the CF transmembrane conductance regulator (CFTR) modulator medicines, which have also been accompanied by new antibiotics, nutritional formulations, as well as advances in the delivery of medicine through nebulization. Many of these have had an influence on the microbiology of the CF lung and the rebalancing of microbial taxa and cell density within the airways. Simultaneously, certain aspects of the new treatments have led to difficulties in PwCF being able to produce sufficient sputum to enable routine microbiological analyses to be performed. Coupled with this, the COVID-19 pandemic has accelerated the emergence of the virtual CF clinical, where individuals with CF do not have to physically travel to CF clinic as frequently as before, with the disadvantage of not producing sputum specimens for routine microbiological analyses. This review examines the interaction between CF mutations and CFTR modulators, with particular focus on CF microbiology.

How to cite this article:
Blevings PJ, Moore JE, Millar BC. Cystic fibrosis: Mutations, modulators and microbiology.J Prev Diagn Treat Strategies Med 2022;1:30-34

How to cite this URL:
Blevings PJ, Moore JE, Millar BC. Cystic fibrosis: Mutations, modulators and microbiology. J Prev Diagn Treat Strategies Med [serial online] 2022 [cited 2022 Jun 26 ];1:30-34
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Cystic fibrosis (CF) is an inherited, autosomal recessive disease which means a child must inherit a copy of the defective gene from both parents to have this progressive disease. It is the most common life-shortening recessive disease for people of Northern European descent[1] and affects over 90,000 individuals worldwide.[2] It is caused by pathogenic mutations in the gene coding for the CF transmembrane conductance regulator (CFTR) protein.[1] The function of the CFTR protein is to form a channel in the membrane of epithelial cells in organs such as the lungs, pancreas, and intestines which allow chloride ions to travel in and out of the cell.[1] It also regulates mucociliary clearance, which is the protective self-clearing mechanism of the airways essential for the removal of respiratory pathogens.[3] Chloride is a component of salt, and without it moving to the cell surface, water is not attracted out of the cell. This causes the buildup of thick, sticky mucus in various organs resulting in many clinical problems such as CF-related diabetes and pancreatic insufficiency. However, respiratory conditions such as infection are the major cause of morbidity and mortality in people with CF (PwCF). For example, in the lungs, the mucus can clog airways, flatten cilia, and trap bacteria and fungi leading to infection, inflammation, and progressive lung disease.[4] The clinical manifestations of CF are shown in [Figure 1].{Figure 1}

Over 75% of PwCF are diagnosed at around 2 years of age through newborn screening and sweat chloride tests, and the average age of survival now exceeds 40 with many living into their 50s.[1] This improvement has been made possible by aggressive treatment of infections with antibiotics and improvements in therapies such as airway clearance, pancreatic enzyme supplements, and more recently CFTR modulator drugs. These drugs target and correct the underlying defect in the CFTR protein caused by the specific mutation and can improve and restore some CFTR functions.[3] However, the treatments for CF can be a large burden to PwCF due to their complexity and length. Treatment regimens may take 2–3 h per day and require the use of complex and specific devices, such as inhalers, which can lead to decreased patient adherence.[4] Therefore, a focus on developing new, less complex treatments, especially with regards to administration, is important and CFTR modulating drugs could help resolve this.


There are more than 1700 recognized pathogenic mutations which cause CF[1],[3] and the most common of these is the F508del mutation found in over 70% of PWCF in the United States.[1] This means the amino acid phenylalanine, in position 508 of the CFTR protein, which is made up of 1480 amino acids, has been deleted so the protein cannot form its correct three-dimensional shape and function properly. The mutations are grouped into six classes according to how the CFTR protein is affected. Classes I-III usually result in no or some residual CFTR function and generally show a severe disease phenotype, whereas classes IV-VI may result in the proteins having residual function and a milder disease phenotype. Knowing the mutation type can benefit the patient as it can affect the treatments available. It can also help guide initial treatment, as some drugs, such as modulators, can target specific classes of CF mutations.


The airways of PwCF are predisposed to respiratory bacterial infections due to the buildup of mucus and impaired mucociliary clearance resulting from defective CFTR protein. Another function of the protein is bicarbonate secretion which neutralizes gastric acid by its high alkaline pH to support absorption and digestion, so the loss of this leads to more acidic airway surfaces. This, combined with increased mucus causing poor clearance of bacteria, may impair airway defenses and make it a more hospitable environment for bacteria.[5] The main bacteria causing infections in CF include Staphylococcus aureus (SA), Haemophilus influenzae, Pseudomonas aeruginosa (PA), and Burkholderia cenocepacia.[5] Chronic bacterial infection is the leading cause of early morbidity and mortality in PwCF and treatment with antibiotics is usually initiated at a young age to control infections and hinder lung damage. During the first 5 years of age, the most abundant species isolated from sputum samples were SA, HA, and PA. After this SA levels remain high and PA continues to increase. As age increases, the diversity of bacteria species in the CF lung decreases and this could be due to increased antibiotic treatment.[6] PA is one of the most common bacteria in CF airways where it can adapt and readily establish chronic infections and around half of all PwCF are infected with this.[5] The percentage of PwCF testing positive for PA increases with age and is found in more than 60% of CF adults, the mean age for the first acquisition, however, is between 6.5 and 7.1 years.[7] In CF, PA contributes to inflammation, airway damage, and poorer prognosis, with chronic infection involving a 10-year reduction in life expectancy, rapid lung function decline, and antibiotic resistance.[8] PA has various forms, and its antimicrobial susceptibility pattern differs between its mucoid and nonmucoid form,[9] with the mucoid being associated with poorer outcomes. Studies show a significant association between mucoidy and chronic infection development.[10] During the development of chronic infection, there is a switch to the mucoid biofilm form which can evade the host immune system and with antibiotics is very difficult to clear.[8] Therefore, there is an emphasis on clearing PA infections as quickly as possible to avoid the emergence of mucoid strains and chronic infections. The fact that infection is such a large problem in CF highlights the importance of further research in this area.

 Antimicrobial Resistance

Respiratory infections occur frequently in PwCF and are treated using antibiotics. However, infections can persist due to antimicrobial resistance (AMR) despite intense treatment. AMR is defined as the ability of an organism to resist the action of an antimicrobial agent to which it was once susceptible[11] and can occur over time on exposure to different antibiotics. Treatment of infections is usually determined by testing the susceptibility of clinical isolates cultured from airway secretions. From these tests, bacteria can be categorized as susceptible, intermediate, or resistant to the antibiotic tested by looking at the minimum inhibitory concentration (MIC). This is the lowest concentration of an antibiotic inhibiting its growth, to the breakpoint concentration of the antibiotic where the bacteria are susceptible and successfully treated. Susceptible bacteria are sensitive to the antibiotic and will be killed or weakened. A resistant bacterium is where the organism's MIC exceeds the breakpoint, so it is unlikely the bacteria will be killed or inhibited. AMR causes significant problems in CF treatment and can be intrinsic through structural or functional bacterial characteristics or acquired.[12] Ultimately, this decreases the number of drugs available. The overuse of antibiotics and repeated treatment cycles has resulted in an increase in multidrug-resistant (MDR) pathogens being isolated from the CF respiratory tract. Their long-term use has also been associated with a reduction in bacterial susceptibility to antibiotics.[13] In fact, some clinical isolates of PA routinely show resistance to all relevant antibiotic classes and this is of great concern.[14] [Figure 2] shows examples of some of the various mechanisms used by PA to become resistant to different classes of antibiotics and wherein the bacterial cell these drugs target.{Figure 2}

Therefore, the failure of antibiotic treatment in airway infections and how to improve it is one of the major focuses in CF research. The most common antibiotics used to treat PA infections are antipseudomonal and include penicillins, aminoglycosides, fluoroquinolones, and monobactams.[15] PA is an opportunistic pathogen targeting immunocompromised individuals, is spread by direct or indirect contact and is usually acquired from the environment. PA has shown intrinsic resistance to many antibiotics and MDR strains are increasing by utilizing acquired and adaptive resistance[11] as illustrated in [Figure 3]. Age appears to affect not only what species of bacteria are present but also their tolerance to antibiotic treatment. For example, isolates of PA and SA from adults are more likely to be MDR and form biofilms.[10] Further research could increase the knowledge of differences in antimicrobial susceptibility patterns between mucoid and nonmucoid strains, improve infection treatment and help select the most appropriate antibiotic to reduce their overuse and resistance development.{Figure 3}

Recently, the arrival of newly developed antibiotics, including beta-lactam + nonbeta-lactam beta-lactamase inhibitors, including meropenem/vaborbactam [Figure 4], ceftazidime/avibactam, as well as new fluoroquinolone, delafloxacin offers new hope to the treatment of some of these multi-and pan-resistant organisms.{Figure 4}

 Cystic Fibrosis Transmembrane Conductance Regulator Modulators

Precision or personalized medicine aims to improve both life expectancy and quality of life for PwCFs and an example of this is CFTR modulating drugs. These drugs are small molecules with the ability to improve or restore the dysfunction caused by specific CF mutations by correcting the malfunctioning protein. There are five main groups based on their actions on CFTR mutations. These groups are potentiators, correctors, stabilizers, read-through agents, and amplifiers.[16] Each class of drug acts differently, for example, potentiators can restore or enhance channel opening, allowing more ions to flow through. This could increase airway hydration and decrease mucus, improving lung function and quality of life. Other mechanisms used include stabilizer drugs which enhance the protein stability by anchoring it to the plasma membrane and preventing its removal and lysosomal degradation. Amplifier drugs increase CFTR mRNA expression to increase the amount of CFTR protein produced. Some research has shown that CFTR modulators could reduce infection of PA and may have a beneficial effect on infections caused by other pathogens. An example of a CFTR modulator is ivacaftor which can bind to the dysfunctional protein, holding the chloride channel open, allowing more ions to pass through, and regulate cell surface fluid. Currently, this drug has been approved for 97 CF mutations and for PwCF above 6 years of age. However, currently, most research has been carried out on developing CFTR modulators for the most common mutation type (F508del), so there are still some mutation types for which no modulating treatment exists. These drugs are also very expensive so are not widely accessible for all PwCF globally. Further research is needed to identify new modulators for rarer CFTR mutations and to enable the costs to be reduced to make them more available.

 Research and Importance

As there is currently no cure for CF, any research which will improve its treatment and the quality of life of PwCF is very important. The availability of antibiotics to treat CF is at its crunch point so increasing the information on which drugs to prescribe and when is essential. This research and more information on antibacterial resistance are needed as PwCF are now living longer, increasing the antibiotic pressure, and leading to the emergence of highly resistant strains. Research studying mutation type and resistance patterns could improve patient outcomes and treatment by discovering more about genotype–phenotype relationships and how disease progression and how AMR differs between different mutations. Studying the phenotype of different bacteria in CF infections could impact antibiotic treatment and improve drug choice. For example, mixed mucoid and nonmucoid communities of PA show a higher tolerance to antibiotics than single phenotype communities. More information on this may help in the selection of the most appropriate antibiotic and the ability to keep some in reserve. Research could also help the development of CFTR modulating drugs, which help restore the underlying genetic defect, which could delay the initial acquisition of PA and reduce the amount of antibiotics needed. This is achieved as the CFTR modulators can alter the lung microbiology and the ability of bacteria to infect and colonize the mucus and epithelium is decreased due to the correction of the protein defect. However, these effects may only be short term as the original bacteria strain remains in high enough numbers to recover and then increase.

In conclusion, now is an exciting time for new and innovative treatment strategies in CF, which will ultimately lead to improved morbidity and mortality of this ancient rare disease.

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Conflicts of interest

There are no conflicts of interest.


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