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Review

Extended-Spectrum Beta-Lactamases (ESBLs) Gene Mutations in Kuwait: How Much Do We Know? Not Much!

by
Ali A. Dashti
* and
Mehrez M. Jadaon
Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, P. O. Box 31470, Sulaibekhat 90805, Kuwait
*
Author to whom correspondence should be addressed.
Bacteria 2025, 4(2), 22; https://doi.org/10.3390/bacteria4020022
Submission received: 5 February 2025 / Revised: 19 March 2025 / Accepted: 3 April 2025 / Published: 30 April 2025
(This article belongs to the Special Issue Bacterial Molecular Biology: Stress Responses and Adaptation)
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Abstract

:
Antibiotic resistance is a major problem worldwide, especially with the overuse and misuse of antibiotics. This makes it more challenging to treat patients infected with antibiotic-resistant bacteria, with more costs on the health system. This review article describes extended-spectrum β-lactam antibiotics as the most used antibacterial agents, and how bacteria developed beta-lactamases (ESBLs) to resist these antibiotics. The review focuses more on the problem of ESBLs in Kuwait to uncover which ESBLs are present and what ESBL gene mutations have been found in this country. The literature review, surprisingly, revealed a limited number of studies in Kuwait on ESBL gene mutations, published over the last 25 years. The results showed that Kuwait has an alarming number of bacterial strains with ESBL gene mutations. These studies reported different mutations in different bacterial strains isolated from different types of specimens, which were collected from different hospitals in Kuwait. The data from these studies were scattered and not linked or analysed together to highlight the big picture of the problem of ESBLs in Kuwait. This review article highlights that the amount of research on ESBLs in Kuwait is not up to the expectations of a country like Kuwait, which has high-standard research facilities. Bearing in mind that the geographic area of Kuwait is relatively small, the authors of this paper think that there might be more β-lactam bacteria spreading in Kuwait, which need to be explored, and that more research and more collaboration are needed among researchers in Kuwait to address this risky situation.

1. Brief History of Antibiotics

In 1928, the Scottish bacteriologist Alexander Fleming discovered that a fungus (Penicillium notatum) could prevent the growth of Staphylococci bacteria in vitro by producing a chemical that had an antibacterial effect. That chemical was called “penicillin”, the first scientifically identified antibiotic in history. After this discovery, extensive studies were conducted to isolate and purify penicillin, and then extract adequate amounts to perform experimental animal studies and clinical trials on humans to prove the efficacy of penicillin as a treatment for bacterial infections, which was achieved by the mid-1940s [1]. Between the 1940s and 1960s, more antibiotics were developed and used for treating patients. That period is usually referred to as the “golden era of antibiotic research”, during which more than half of the currently known antibiotics were developed and used as antibacterial treatments [1,2]. More than 20 new classes of antibiotics were introduced during that era [3]. This had an enormous positive effect in saving the lives of millions of people worldwide. For example, by the year 1944, the rate of production of penicillin was over a billion doses yearly [4]. The survival rate of bacterial pneumonia dramatically increased from 20% to 85% during that period. It is estimated that the use of antibiotics extended the average human lifespan by 23 years. Although the main purpose of antibiotics is treating patients with bacterial infections, it is also widely used as preventive medicine in cases of surgery, cancer, organ transplantation, pre-term babies, and so on [2].

2. Antibiotic Resistance

After the development and wide use of antibiotics in treating bacterial infections, several bacteria could evolve and develop mechanisms to resist the actions of antibiotics, a phenomenon known currently as “antibiotic resistance”. Surprisingly, this happened very quickly after the widespread use of penicillin, in the early 1940s, when strains of E. coli and S. aureus were found to be penicillin-resistant [1,5,6]. Still, many scientists found indications that such resistance was buried inside the bacterial genome but were activated after the exposure to antibiotics [7]. This encouraged scientists to develop new types of antibiotics that could overcome such resistance. Still, the battle between bacteria and antibiotics continues and more bacteria are found to resist more antibiotics. Common mechanisms used by the bacteria to resist antibiotics include inactivation or breakdown of the antibiotics by bacterial enzymes, changing the bacterial components that are targeted by the antibiotics, or changing the bacterial membrane permeability of the antibiotics, by preventing the intake of antibiotics or increasing antibiotic efflux out of the bacterial cell [7,8,9].
Antibiotic resistance has become a major problem worldwide, especially with the overuse and misuse of antibiotics. What makes this problem more challenging is that bacteria were found to transfer resistance genes among themselves, a phenomenon known as horizontal gene transfer (HGT) [9]. Currently, a good number of bacteria are found to be resistant to almost all available antibiotics; such multidrug-resistant bacteria are termed “superbugs” [1]. This puts more challenges on treating patients infected with these superbugs. For example, it was estimated that, yearly, more than 2 million people become infected with antibiotic-resistant bacteria in the US alone, leading to more than 23,000 deaths, with a cost of US$7000–29,000 per patient [9]. In the European Union, more than 25,000 patients die of infections with antibiotic-resistant bacteria every year [7]. Globally, antibiotic-resistant bacterial infections caused 1.27 million deaths in 2019 [10]. In addition, the World Bank estimates that this problem could cost health systems an additional US$ 1 trillion in healthcare costs by the year 2050 [11].
In this review paper, the authors focused on antibiotic resistance due to extended-spectrum beta-lactamase (ESBL) gene mutations, with special attention to the situation in Kuwait where the authors live and work.

3. β-Lactam Molecules

In the mid-1940s, the chemical structure of penicillin was determined [12,13] to have a core of a four-membered lactam ring (cyclic amide), with a carbonyl group, as depicted in Figure 1.
The lactam ring in penicillin is of the β type, which consists of four atoms: three carbon atoms and one nitrogen atom, forming a square-like ring. The nitrogen atom is attached to the β-carbon atom of the ring [4,14,15]. Within a few years after the discovery of penicillin, more similar molecules were found from natural sources (bacterial or fungal), or were synthesised and had similar chemical structures to penicillin. All these have the β-lactam ring as the essential core structure, with additional ring structures directly connected to the β-lactam ring, except for monobactams. Examples of these so called β-lactam antibiotics include second-generation penicillins (like oxacillin, methicillin, and dicloxacillin) and third-generation penicillins (like amoxicillin and ampicillin). Moreover, other classes of β-lactam molecules were discovered and introduced for clinical use, which had chemical alterations in the core β-lactam structure, increasing the spectrum of their activity. Since the late 1970s, more of these beta-lactam antibiotics have been developed and introduced, including the penams, penems, cephems, carbapenems, and monobactams [1,4,15,16].
β-lactam antibiotics are currently the most used antibacterial agents to treat infections. For example, they account for two-thirds of all prescriptions for injectable antibiotics in the USA, half of which are cephalosporins [14].

4. How Do β-Lactam Antibiotics Work?

The main bactericidal effect of β-lactam antibiotics is exerted by disturbing the synthesis of bacterial cell wall. The bacterial cell wall is made up of peptidoglycans, which give the bacterial cell its shape and integrity, and protect it from outside attacks and osmotic stress [1]. Peptidoglycans are continuously made and remodelled during bacterial life and division, and these molecules should be cross-linked with peptide bonds to form a firm network of proteins that give the bacterial cell wall its strength and stability. This cross-linking is performed by specific bacterial enzymes called transpeptidases (also known as penicillin-binding proteins; PBPs) [1,14]. Different bacterial species have different numbers of transpeptidases, usually 3 to 8 enzymes [14]. Transpeptidases recognise dipeptide moieties in glycans and form peptide linkage among the peptidoglycans in the bacterial cell wall [15]. β-lactam antibiotics, through their β-lactam rings, can bind to the active site of the transpeptidases, usually a serine, preventing them from cross-linking the peptidoglycans. This disrupts the making of the bacterial cell wall, and eventually prevents bacterial growth and proliferation. In addition, the bacteria will be susceptible to lysis due to osmosis [1,15]. In short, β-lactam antibiotics prevent bacterial proliferation and kill the infective bacteria, eliminating the infection in the patient. Another advantage of β-lactam antibiotics is that they only attack the cell wall of prokaryotic cells (the bacterial cells). Therefore, the eukaryotic cells (including human cells) will not be affected [1].

5. ESBLs

The introduction of antibiotics as weapons against bacteria ignited a defensive reaction from the bacteria, which rendered some bacteria resistant to the bactericidal action of antibiotics. Regarding lactam antibiotics, bacteria started producing enzymes that could inactivate the action of lactam. As penicillin was the first antibiotic to be used in treating infections, penicillin resistance was the first reported antibiotic resistance; as was mentioned earlier, it was reported just a few years after the widespread use of penicillin [1,5,6]. Penicillin-resistant bacteria managed to counterattack penicillin by producing penicillinases, an enzyme that can hydrolyse the lactam of the antibiotic, leading to the inactivation of penicillin, as seen in Figure 2.
This involves the formation of an acyl-enzyme intermediate between the serine residue of the penicillinase and the carbonyl carbon of the lactam ring, which is then hydrolysed, and hence the antibiotic becomes inactivated [17,18]. Penicillin resistance spread quickly. For example, by the late 1960s, more than 80 percent of both community- and hospital-acquired strains of S. aureus were penicillin resistant [1]. An increase in penicillin-resistance has compromised the use of penicillin as a single therapeutic agent, and currently, there are limited therapeutic options that can use penicillin as monotherapy [14].
With the emergence of penicillin resistance, efforts succeeded to extract or semi-synthesise new antibiotics with modifications to penicillin, retaining the lactam core to attack bacterial cell wall synthesis, and, at the same time, these new antibiotics were not inactivated by penicillinase [1,4,15,16]. However, with every introduction of new antibiotics, bacteria were found to develop resistance by producing enzymes that inactivate these antibiotics in a similar way to penicillinase [17,18]. Enzymes against lactam antibiotics were called lactamases. With the development of new generations of antibiotics, and new types of lactam antibiotics against a broad spectrum of bacteria, the bacterial lactamases are currently known as extended-spectrum beta-lactamases (ESBLs). These hydrolytic enzymes can break down and inactivate a wide range of lactam antibiotics, which makes these antibiotics ineffective in treating infections by ESBL-producing bacteria [17].

6. Classification of ESBLs

Due to the large number of reported ESBLs, which are continuously increasing, there were many attempts to classify these ESBLs [19,20,21]. Ambler (1980) proposed four classes based on amino acid sequencing, which are now known as Ambler classes A, B, C, and D [22]. Another classification was made by Bush et al. (1995), which was based on the functional properties of the enzymes, and it included four groups and many subgroups [23]. These classifications are widely used in microbiology. On the other hand, the advancement of molecular biology techniques allowed thorough exploration of the genetics of ESBLs, and therefore it is also common to refer to different ESBLs based on their genomes, as explained next.

7. Genetics of ESBLs

Genes of ESBLs (generally referred to as bla genes) are usually encoded on plasmids, which explains the transfer of these genes among bacteria leading to the rapid and wide spread of antibiotic resistance. The ESBL genes have undergone several mutations over time, resulting in a wide array of ESBL variants with different substrate specificities and hydrolytic activities against lactam antibiotics [21]. ESBLs against most lactam antibiotics were found to evolve. These were also found to be transferred within the bacterial species, or even across different species, conferring lactam resistance on more bacteria. For example, CTX-M-15, which is a member of the CTX family of ESBLs, was initially found in E. coli, but now it has been reported in other members of Enterobacteriaceae worldwide [24,25]. Studies have found different ESBL genes that were grouped into several families, the most famous being the TEM (Temoniera), SHV (Sulfhydryl Variable), and CTX-M (Cefotaximase-Munich) families. Others include OXA, GES, PER, VEB, TLA, and many other families [19,21,26]. The first TEM was reported in an E. coli isolate in 1965, and is therefore referred to as TEM-1 [27]. The SHV family is derived from Klebsiella species since its progenitor SHV-1 is universally present in that species [28]. CTX-M has been found mainly in isolates of Salmonella, Typhimurium, and E. coli, as well as other species of Enterobacteriaceae [19]. CTX-M is currently the most common variant of ESBLs [19,21]. Studies revealed several mutations in these genes leading to ESBL variants in different antibiotic-resistant bacterial strains. The continuous discovery of large numbers of new mutations created challenges in coordinating proper nomenclature for these mutations [20]. In the mid- to late-1990s, George Jacoby and Lahay Clinic created a website to name and record new ESBL gene mutations [29]. However, this website was closed in 2015 and the databases were transferred to the National Center for Biotechnology Information (NCBI), which has now become responsible for β-lactamase numerology [30].

8. ESBLs Mutations in Kuwait

In the years 2010 and 2011, the authors of this paper discovered two new SHV mutations in antibiotic-resistant bacteria (K. pneumoniae and E. coli), which were assigned the nomenclature SHV-112 and SHV-122, respectively [31,32]. They made their discoveries in bacterial strains isolated from clinical samples in Kuwait, which is a Middle Eastern country with a relatively small area, but a very developed healthcare system. The authors thought to revisit ESBLs 15 years after their discoveries of SHV-112 and SHV-122 to explore the current situation in Kuwait regarding ESBLs and β-lactam resistance, and examine what kind of ESBL mutations have been found so far in Kuwait. The authors of the paper have contributed to the findings of mutations in ESBL genes, namely by discovering SHV-112 and SHV-122 in bacterial strains in Kuwait [31,32]; these discoveries happened in 2010 and 2011, respectively. Kuwait is a Middle Eastern country, with a relatively small area, but a very developed healthcare system. Lactam resistance was noticed in clinical samples from different patients in Kuwaiti hospitals. The authors thought to revisit ESBLs 15 years after their discoveries of SHV-112 and SHV-122 to explore the current situation in Kuwait concerning ESBLs and lactam resistance is, and what kind of ESBL mutations were found and may be prevalent in Kuwait.

Search Strategy

The authors used PubMed to search for publications on the ESBLs in Kuwait. The search terms were “Extended-spectrum beta-lactamases in Kuwait” or “ESBLs in Kuwait”. Up to the time of the writing of this review article (August 2024), a total of 41 publications were found. However, adding the word “genes” to the search bar in PubMed narrowed the results down to 20 publications. Moreover, adding the word “mutations” or even using that word without “genes” brought down the results to four publications only: two of these were research papers published in 2010 by the authors of this review article [31,33]; one paper was a review article by the late Dr. Patrick West, who worked in Kuwait during the publishing of his paper in the year 2000—but the paper itself was a general review on ESBL genes, and not specifically about Kuwait [34]; the last article was a recent research paper published in 2023 [35]. It was surprising to find more than 10-year gaps in publications on ESBL gene mutations from 2000 to 2010, and then in 2023. However, by carefully checking the 41 publications found during the first search, the authors found that 9 papers did mention some results on ESBL genes, but were not picked up when the word “genes” was added to the search process. Out of the forty-one papers, two were review articles, one of them being the one mentioned above which was published by Dr. West in the year 2000 [34]. The other review article was a gathering of results of publications from the six Arab countries present in the Arabian Gulf [36] (which is also referred to as the Persian Gulf in many geographic maps). Among the remaining 39 research publications, 8 studies were not conducted on samples from Kuwait, but some of the co-authors had affiliations with Kuwait and therefore were mentioned by the PubMed search engine. Among the remaining 31 papers, only 13 papers included some molecular techniques to confirm ESBL genes and variants in their samples, but these papers were more focused and elaborated on antibiotic resistance using conventional microbiology lab tests. Figure 3 presents a flowchart showing the search strategy and the selection process, as well as the exclusion criteria, to end up with these 13 publications. Table 1 gives a summary of the findings of these 13 research articles that included data on ESBL genes and variants obtained using molecular techniques. Figure 4 shows the timeline of published findings of ESBL gene and variants between the years 2007 and 2023.
It may be noted from Table 1 and Figure 4 that the number of studies on ESBL gene mutations in Kuwait was relatively small. The results, available from the limited number of studies published so far, show that Kuwait has an alarming number of bacterial strains with ESBL gene mutations. However, the data were scattered and not linked nor analysed together to highlight the big picture of the problem of ESBLs in Kuwait. What is also alarming are the findings by a recent study which reported multidrug-resistant E. coli in samples obtained from three sewage sites in Kuwait, many of which showed ESBL production with the presence of TEM and CTX-M [47]. What is more worrying is that 25% of the sewage in Kuwait is usually discharged directly into the Kuwait sea water, where a lot of fishing for food as well as recreational activities happen [47]. This accounts for a high risk of infections with multidrug-resistant bacteria—at least E. coli, according to that study—that may be difficult to treat with fewer treatment options for patients and increase morbidity and mortality rates.
The main finding in this review paper is that there is a limited number of studies on ESBL genetics in Kuwait (13 studies over a period of 17 years), which is ringing an alarming bell. Several international studies have shown that the prevalence of ESBL-producing bacteria has increased over the years. For example, an American study found that the prevalence of ESBL-producing E. coli has increased in both community-onset and healthcare-onset infections from 2014 to 2020 by 0.91% and 2.31% per year, respectively [48]. During the abovementioned years, only a single study was conducted in Kuwait, as shown in Figure 4. Another Canadian study found an increase in the prevalence of E. coli (3.4% to 11.1%) and K. pneumoniae (1.3% to 9.7%) from 2007 until 2016 [49]. Similar findings were reported in Europe [50]. Globally, an increase in the prevalence of ESBL-producing bacteria was found in healthcare settings (3-fold) and community settings (10-fold) over the period of 2001–2005 to 2016–2020 [51]. Such a trend could not be established in Kuwait because, again, there is a limited number of studies in this country.
The authors of this paper encourage conducting more elaborate studies on ESBLs and their gene mutations in Kuwait, and they believe that more collaboration is needed among Kuwaiti microbiologists and clinicians to address the problem of antibiotic resistance in Kuwait. Such efforts should inform appropriate health plans and strategies to deal with this problem in Kuwait. This should be addressed today and not tomorrow. It is also recommended to collaborate with researchers from the other Arabian Gulf countries to find any spreading of ESBLs across the borders and to unite the efforts to address the problem of antibiotic resistance in this geographic part of the world.

9. Conclusions

To conclude, this review article has explained the antibiotic resistance of ESBLs, especially in the country of Kuwait. Bacteria with resistance to extended-spectrum β-lactam antibiotics have increased over the years, creating a risky treatment situation around the world. However, the number of studies accomplished about this bacterial resistance is quite limited in the country of Kuwait, which means there is a pathway that needs to be taken for more collaborative studies in this respect to explore and address this situation in Kuwait.

Author Contributions

Writing—original draft preparation, A.A.D. and M.M.J.; writing—review and editing, A.A.D. and M.M.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. The structure of lactam molecules. (a) The general structure showing the lactam ring, (b) the structure of 2-azetidinone as the simplest lactam, and (c) the structure of penicillin as an example of lactams. The illustration was drawn by the authors of this paper.
Figure 1. The structure of lactam molecules. (a) The general structure showing the lactam ring, (b) the structure of 2-azetidinone as the simplest lactam, and (c) the structure of penicillin as an example of lactams. The illustration was drawn by the authors of this paper.
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Figure 2. Hydrolysis of lactam ring as method of penicillin-resistance exerted by bacteria. Illustration is drawn by authors of this paper.
Figure 2. Hydrolysis of lactam ring as method of penicillin-resistance exerted by bacteria. Illustration is drawn by authors of this paper.
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Figure 3. A flowchart showing the searching strategy followed in this paper. It shows how PubMed was used to search for publications on ESBL genes in Kuwait, the search terms, and the selection criteria. It may be noticed that the authors also checked the publications manually to exclude review articles and papers that did not include samples from Kuwait, and to include only the papers that performed molecular techniques to confirm genetic mutations. The final result was the inclusion of 13 publications.
Figure 3. A flowchart showing the searching strategy followed in this paper. It shows how PubMed was used to search for publications on ESBL genes in Kuwait, the search terms, and the selection criteria. It may be noticed that the authors also checked the publications manually to exclude review articles and papers that did not include samples from Kuwait, and to include only the papers that performed molecular techniques to confirm genetic mutations. The final result was the inclusion of 13 publications.
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Figure 4. The timeline of published findings of ESBL gene and variants in Kuwait between the years 2007 and 2023, showing the years of publications and the genes variants reported by 13 studies, which are described in Table 1. It should be noted that CMY-2, ACT, and KPC are not ESBL, but were added here because they were reported by the corresponding articles.
Figure 4. The timeline of published findings of ESBL gene and variants in Kuwait between the years 2007 and 2023, showing the years of publications and the genes variants reported by 13 studies, which are described in Table 1. It should be noted that CMY-2, ACT, and KPC are not ESBL, but were added here because they were reported by the corresponding articles.
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Table 1. The summary of the findings of 13 research articles that included data on ESBL genes and variants obtained using molecular techniques in Kuwait, as found by searching PubMed. CMY-2, ACT, and KPC are not ESBL, but were added here because they were reported by the articles mentioned next to each one. * This was an international study from different countries. Only one case was included from Kuwait.
Table 1. The summary of the findings of 13 research articles that included data on ESBL genes and variants obtained using molecular techniques in Kuwait, as found by searching PubMed. CMY-2, ACT, and KPC are not ESBL, but were added here because they were reported by the articles mentioned next to each one. * This was an international study from different countries. Only one case was included from Kuwait.
Years of TestingBacteriaHospital in KuwaitESBL Genes Reported (Percentage Not Shown)Reference (Publication Year)
2003
1994 to 1996		E. coliAl-Amiri
Al-Farwania		TEM, SHV (general)[37] (2007)
2002 to 2004E. cloacae, C. freundiiMubarak
Al-Kabir		SHV-12, VEB-1b[38] (2007)
2003 to 2006Salmonella spp.Mubarak Al-Kabir
Infectious Diseases H.		TEM, CTX-M-15[39] (2008)
2005 to 2006K. pneumoniaeAl-JahraTEM-1, SHV-112,
CTX-M-15-like		[33] (2010)
2010K. pneumoniaeAl-AmiriSHV-112[31] (2010)
2008K. pneumoniaeMubarak Al-KabeerTEM-1, CTX-M-15[40] (2011)
2008E. coliMubarak Al-Kabeer
Al-Amiri
Al-Sabah
Al-Adan
Al-Jahra
Ibn Sina
Al-Farwaniya
Maternity		TEM, SHV (general),
CTX-M (−15, −14, −14b, TOHO-1)		[41] (2011)
2007 to 2008A. baumanniiMubarak Al-Kabeer
Al-Sabah
Al-Adan
Al-Jahra
Al-Babtain
Al- Razi		GES-11, GES-14, OXA-23
OXA-51-like (−74, −66, −71, −98)		[42] (2013)
Non-specifiedK. pneumoniaeAl-Amiri
Al-Adan,
Al-Ahmadi (Kuwait Oil
Company H.)		TEM-1, SHV,
CTX-M (−2, −15)		[43] (2015)
2012 to 2019E. coli, K. pneumoniae3 non-specified hospitalsCTX-M-15[44] (2021)
2020 to 2021E. coli, K. pneumoniaeMubarak Al-Kabeer
Ibn Sina
Al-Babtain		TEM-1, SHV-11/-12,
CTX-M-15, OXA-1/-48, KPC-2/-29, CMY-4/-6, OKP-B, ACT, EC		[45] (2022)
2020Enterobacteriaceae spp. (mostly E. coli, Klebsiella spp., Enterobacter spp.)Al-FarwaniyaTEM, SHV, CTX-M (general)[35] (2023)
2017 to 2022E. coliNon-specifiedCMY-2[46] (2023) *
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MDPI and ACS Style

Dashti, A.A.; Jadaon, M.M. Extended-Spectrum Beta-Lactamases (ESBLs) Gene Mutations in Kuwait: How Much Do We Know? Not Much! Bacteria 2025, 4, 22. https://doi.org/10.3390/bacteria4020022

AMA Style

Dashti AA, Jadaon MM. Extended-Spectrum Beta-Lactamases (ESBLs) Gene Mutations in Kuwait: How Much Do We Know? Not Much! Bacteria. 2025; 4(2):22. https://doi.org/10.3390/bacteria4020022

Chicago/Turabian Style

Dashti, Ali A., and Mehrez M. Jadaon. 2025. "Extended-Spectrum Beta-Lactamases (ESBLs) Gene Mutations in Kuwait: How Much Do We Know? Not Much!" Bacteria 4, no. 2: 22. https://doi.org/10.3390/bacteria4020022

APA Style

Dashti, A. A., & Jadaon, M. M. (2025). Extended-Spectrum Beta-Lactamases (ESBLs) Gene Mutations in Kuwait: How Much Do We Know? Not Much! Bacteria, 4(2), 22. https://doi.org/10.3390/bacteria4020022

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