Low Fitness Cost of the Multidrug Resistance Gene
            <i>cfr</i>

LaMarre, Jacqueline M.; Locke, Jeffrey B.; Shaw, Karen Joy; Mankin, Alexander S.

doi:10.1128/aac.00153-11

Cited by 64 publications

(41 citation statements)

References 47 publications

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“…Addition of the Cfr-expressing plasmid to the strains produced only a tiny doubling time increase (1 to 3 min). This is as expected from a study of Staphylococcus aureus (22) and our unpublished results obtained with E. coli, showing that Cfr expression does not significantly affect the bacterial growth rate.…”

Section: Resultssupporting

confidence: 75%

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

Pakuła

Hansen

Vester

2017

Antimicrob Agents Chemother

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Several groups of antibiotics inhibit bacterial growth by binding to bacterial ribosomes. Mutations in ribosomal protein L3 have been associated with resistance to linezolid and tiamulin, which both bind at the peptidyl transferase center in the ribosome. Resistance to these and other antibiotics also occurs through methylation of 23S rRNA at position A2503 by the methyltransferase Cfr. The mutations in L3 and the cfr gene have been found together in clinical isolates, raising the question of whether they have a combined effect on antibiotic resistance or growth. We transformed a plasmid-borne cfr gene into a uL3-depleted Escherichia coli strain containing either wild-type L3 or L3 with one of seven mutations, G147R, Q148F, N149S, N149D, N149R, Q150L, or T151P, expressed from plasmid-carried rplC genes. The L3 mutations are well tolerated, with small to moderate growth rate decreases. The presence of Cfr has a very minor influence on the growth rate. The resistance of the transformants to linezolid, tiamulin, florfenicol, and Synercid (a combination of quinupristin and dalfopristin [Q-D]) was measured by MIC assays. The resistance from Cfr was, in all cases, stronger than the effects of the L3 mutations, but various effects were obtained with the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. Linezolid and tiamulin susceptibility varied greatly among the L3 mutations, while no significant effects on florfenicol and Q-D susceptibility were seen. This study underscores the complex interplay between various resistance mechanisms and cross-resistance, even from antibiotics with overlapping binding sites.KEYWORDS Cfr, L3 mutations, antibiotic resistance, linezolid resistance, tiamulin resistance O ver time, more and more mutations in bacterial ribosomal protein L3 (renamed uL3 in accordance with the new universal naming of ribosomal proteins [1]) have been associated with resistance to the antibiotics linezolid (LZD, an oxazolidinone) and tiamulin (TIA, a pleuromutilin). These drugs have overlapping binding sites at the peptidyl transferase center (PTC) in the ribosome (Fig. 1). Specific mutations of 23S rRNA and methylation at position 2503 also cause resistance to these antibiotics, as reviewed in references 2-4. The main part of L3 is positioned on the surface of the 50S ribosomal subunit, but a branched loop extends close to the PTC (Fig. 1), the binding site for various ribosomal antibiotics. The first L3 resistance mutation reported in bacteria was from Escherichia coli selected with TIA, and its role in resistance was verified by genetic evidence (5). Since then, L3 mutations have been associated with resistance to LZD, TIA/valnemulin, and anisomycin, as reviewed in references 2 and 6. Relationships between L3 mutations and antibiotic resistance have been reported in Brachyspira, Staphylococcus, E. coli, and Mycobacterium tuberculosis, but many of the findings lack genetic verification. Our recent study (6) demonstrated a clear antibiotic

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Section: Resultssupporting

confidence: 75%

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

Pakuła

Hansen

Vester

2017

Antimicrob Agents Chemother

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“…This resistance is more worrisome than the mutation‐based mechanism since it is horizontally transferable and carries a low fitness cost 32, 33. Mechanistically, the methyltransferase Cfr, through C8 methylation of the key residue A2503Ec in the 23S rRNA, greatly reduces susceptibility to a wide range of ribosome‐targeting antibiotics, including amphenicols, lincosamides, pleuromutilins, streptogramin A, 16‐membered macrolides, and linezolid 34.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…On the other hand, cf r and fexA were located on a plasmid carried transposon in Staphylococcus isolates from different animal sources. 45,46 Two plasmid-borne sul genes sul1 and sul2 were detected in all samples of the 11 broiler feedlots, indicating that sul genes are distributed widely in broiler feedlots environments. The sul1 gene had higher abundance than sul2 in almost all samples, which is similar to the distribution of sul genes in sulfonamideresistant bacteria from swine farm wastewaters.…”

Section: Dissemination Of Args In the Broiler Feedlotsmentioning

confidence: 99%

Dissemination of Antibiotic Resistance Genes in Representative Broiler Feedlots Environments: Identification of Indicator ARGs and Correlations with Environmental Variables

Liu

et al. 2014

Environ. Sci. Technol.

227

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Livestock operations are known to harbor elevated levels of antibiotic resistance genes (ARGs) that may pose a threat to public health. Broiler feedlots may represent an important source of ARGs in the environment. However, the prevalence and dissemination mechanisms of various types of ARGs in the environment of broiler feedlots have not previously been identified. We examined the occurrence, abundance and variation of ARGs conferring resistance to chloramphenicols, sulfonamides and tetracyclines in the environments of two representative types of broiler feedlots (free range and indoor) by quantitative PCR, and assessed their dissemination mechanisms. The results showed the prevalence of various types of ARGs in the environmental samples of the broiler feedlots including manure/litter, soil, sediment, and water samples, with the first report of five chloramphenicol resistance genes (cmlA, floR, fexA, cf r, and fexB) in broiler feedlots. Overall, chloramphenicol resistance genes and sulfonamides sul genes were more abundant than tetracyclines tet genes. The ARG abundances in the samples from indoor boiler feedlots were generally different to the free range feedlots, suggesting the importance of feeding operations in ARG dissemination. Pearson correlation analysis showed significant correlations between ARGs and mobile genetic element genes (int1 and int2), and between the different classes of ARGs themselves, revealing the roles of horizontal gene transfer and coselection for ARG dissemination in the environment. Further regression analysis revealed that fexA, sul1 and tetW could be reliable indicator genes to surrogate anthropogenic sources of ARGs in boiler feedlots (correlations of fexA, sul1 and tetW to all ARGs: R = 0.95, 0.96 and 0.86, p < 0.01). Meanwhile, significant correlations were also identified between indicator ARGs and their corresponding antibiotics. In addition, some ARGs were significantly correlated with typical metals (e.g., Cu, Zn, and As with fexA, fexB, cf r, sul1, tetW, tetO, tetS: R = 0.52−0.71) and some environmental parameters (e.g., TOC, TN, TP, NH 3 −N with fexA, fexB, cf r, sul1, tetW, tetO, tetQ, tetS: R = 0.53−0.87) (p < 0.01). Further redundancy analysis demonstrated that the distribution and transportation of ARGs from the boiler feedlots to the receiving environments were correlated with environmental variables. The findings highlight the contribution of some chemicals such as antibiotics and metals to the development of ARGs in broiler feedlots environments; and the observed ARG dissemination mechanism in the broiler feedlots facilitates the development of effective mitigation measures.

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Low Fitness Cost of the Multidrug Resistance Gene cfr

Cited by 64 publications

References 47 publications

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

Targeting Antibiotic Resistance

Dissemination of Antibiotic Resistance Genes in Representative Broiler Feedlots Environments: Identification of Indicator ARGs and Correlations with Environmental Variables

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