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Characterization of a Novel Gene, Srpa, Conferring Resistance to Streptogramin A, 2 Pleuromutilins, and Lincosamides in Streptococcus Suis1

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Characterization of a Novel Gene, Srpa, Conferring Resistance to Streptogramin A, 2 Pleuromutilins, and Lincosamides in Streptococcus Suis1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.07.241059; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Characterization of a novel gene, srpA, conferring resistance to streptogramin A, 2 pleuromutilins, and lincosamides in Streptococcus suis1 3 Chaoyang Zhang,a Lu Liu,a Peng Zhang,a Jingpo Cui,a Xiaoxia Qin, a Lichao Ma,a Kun Han,a 4 Zhanhui Wang b, Shaolin Wang b, Shuangyang Ding b, Zhangqi Shen a,b 5 6 a Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary 7 Medicine, China Agricultural University, Beijing, China. 8 b Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety and Beijing 9 Laboratory for Food Quality and Safety, China Agricultural University, Beijing, China 10 11 Address correspondence to Zhangqi Shen, [email protected]; 12 13 14 15 1 Abbreviations: Multidrug-resistant (MDR), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), peptidyl-transferase center (PTC), transmembrane domains (TMDs), valnemulin (VAL), enrofloxacin (ENR), fluorescence polarization immunoassay (FPIA), nucleotide-binding sites (NBSs), fluorescence polarization (FP), carbonyl cyanide m- chlorophenylhydrazone (CCCP) bioRxiv preprint doi: https://doi.org/10.1101/2020.08.07.241059; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 16 Abstract 17 Antimicrobial resistance is undoubtedly one of the greatest global health threats. The emergence of 18 multidrug-resistant (MDR) gram-positive pathogens, like methicillin-resistant Staphylococcus 19 aureus, vancomycin-resistant Enterococcus faecium, and β-lactamase-resistant Streptococcus 20 pneumonia, has severely limited our antibiotic arsenal. Numerous ribosome-targeting antibiotics, 21 especially pleuromutilins, oxazolidinones, and streptogramins, are viewed as promising alternatives 22 against aggressive MDR pathogens. In this study, we identified a new ABC-F family determinant, 23 srpA, in Streptococcus suis by a comparative analysis of whole genome sequences of tiamulin- 24 resistant and -sensitive bacteria. Functional cloning confirmed that the deduced gene can mediate 25 cross-resistance to pleuromutilins, lincosamides, and streptogramin A in S. suis and S. aureus. A 26 sequence alignment revealed that srpA shares the highest amino acid identity with Vga(E) (36%) and 27 shows canonical characteristics of ABC-F family members. In SrpA–ribosome docked compounds, 28 the extended loop region of SrpA approaches the valnemulin binding pocket in the ribosome 29 peptidyl-transferase center and competes with bound valnemulin. A detailed mutational analysis of 30 the loop residues confirmed that this domain is crucial for SrpA activity, as substitutions or 31 truncations of this region affect the efficiency and specificity of antibiotic resistance. A ribosome 32 binding assay supported the protective effects of SrpA on the ribosome by preventing antibiotic 33 binding as well as displacing bound drugs. These findings clarify the mechanisms underlying 34 resistance to ribosomal antibiotics. 35 Keywords: SrpA, Streptococcus suis, antibiotic resistance, ribosome, ABC-F family proteins. bioRxiv preprint doi: https://doi.org/10.1101/2020.08.07.241059; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 36 1. Introduction 37 Antimicrobial resistance is now recognized as one of the most serious global threats to human and 38 animal health in the 21st century, and the emergence of multidrug-resistant (MDR) pathogens threatens 39 to cause regression to the pre-antibiotic era [1, 2]. Consequently, infections caused by highly resistant 40 gram-positive organisms, such as staphylococci, streptococci, and enterococci, are considered a major 41 public health issue [3]. In particular, the emergence of methicillin-resistant Staphylococcus aureus 42 (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactamase-resistant 43 Streptococcus pneumonia have made treatment of the infections very challenging. 44 More than half of the antibiotics in use target the bacterial ribosome; these inhibitors can paralyze 45 protein synthesis by interacting with the 30S small subunit or 50S large subunit [4-6]. Several 46 ribosome-targeting antibiotics (macrolides, pleuromutilins, lincosamides, streptogramins, and 47 oxazolidinones) are viewed as effective alternatives and last resort drugs for human use (Table S1) 48 [2, 7, 8]. Pleuromutilins were discovered as natural agents in 1951; the C-14 derivatives tiamulin and 49 valnemulin are widely used in veterinary medicine, and retapamulin and lefamulin are approved for 50 human use against MRSA or β-lactamase-resistant streptococci [9, 10]. Structural characterization 51 has revealed that pleuromutilins can bind to the peptidyl-transferase center (PTC) of 23S rRNA, 52 thereby preventing the correct positioning of acceptor or donor substrates at A-sites and P-sites [10- 53 14]. 54 Accumulating evidence suggests that the resistance of gram-positive pathogens to pleuromutilins is 55 increasing; notably, most isolates show cross-resistance to pleuromutilins, lincosamides, and 56 streptogramins A, thereby exhibiting the PLSA phenotype [15-18]. Resistance to pleuromutilins is 57 commonly attributed to the acquisition of endogenous mutations in 23S rRNA or horizontally 58 transmitted resistance determinants, such as the rRNA methyltransferase Cfr or the antibiotic 59 resistance ATP-binding cassette (ABC) F family proteins—Vga/Lsa/Sal/VmlR [4, 7, 19]. Antibiotic bioRxiv preprint doi: https://doi.org/10.1101/2020.08.07.241059; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 60 resistance ABC-F family genes have been found in the genomes of numerous pathogens and confer 61 resistance to a broad range of clinically relevant antibiotics targeting the ribosomes [20-22]. Unlike 62 other ABC superfamily members that actively pump drugs out of the membranes, the ABC-F family 63 proteins do not fuse to transmembrane domains (TMDs). Accordingly, the mechanism by which 64 ABC-F members mediate antibiotic resistance has been a subject of long-standing controversy. 65 Cryo-electron microscopy (cryo-EM) structures of two ABC-F proteins, MsrE and VmlR, bound to 66 the ribosome, indicate that the protection is conferred by interactions with the antibiotic-stalled 67 ribosomes and displacement of the bound drug [23-25]. 68 Streptococcus suis is an emerging zoonotic pathogen; the largest outbreak in humans occurred in 69 China in 2005 (204 infections and 38 deaths) [26]. S. suis may also act as a resistance gene reservoir, 70 contributing to the spread of resistance genes to major streptococcal pathogens [27, 28]. During a 71 surveillance study of S. suis resistance in China, 42 tiamulin-resistant isolates did not harbor known 72 resistance determinants. In this study, we identified and characterized a novel antibiotic resistance 73 determinant, srpA (S. suis Ribosome Protective ABC-F family protein), including analyses of its 74 physicochemical properties and molecular mechanisms. Our comprehensive analyses, including 75 functional cloning, homology modeling, molecular docking, mutagenic analyses, and ribosome 76 binding assays provide a detailed understanding of the mechanisms by which SrpA confers antibiotic 77 resistance. 78 Materials and methods 79 2.1.Bacterial strains 80 A total of 166 S. suis were collected from five provinces in China in 2018, and 72 isolates showed 81 tiamulin resistance. Escherichia coli BL21, DH5a, S. aureus RN4220, and S. suis SD1BY15 were 82 used as hosts for cloning. bioRxiv preprint doi: https://doi.org/10.1101/2020.08.07.241059; this version posted August 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 83 2.2. Bioinformatics and sequence analysis 84 The genomic DNA of all tested isolates was extracted as described previously and subjected to 85 whole-genome sequencing [29]. A pan-genome analysis was conducted by the rapid Roary pipeline 86 for 42 resistant candidates (without known determinants) and 94 susceptible strains [30]. The data 87 were processed using the Python package pandas, and ORFs annotated as putative ABC transporter 88 ATP-binding proteins in more than 10 isolates were extracted. The results were visualized using 89 Matplotlib and Seaborn. MEGA7.0 was used to generate a phylogenetic tree of ABC-F family 90 proteins by the neighbor-joining method (Bootstrap: 1000 times) [31]. Sequence logos of 91 corresponding proteins were generated using online tools [32]. The nucleotide sequence of srpA and 92 flanking regions has been deposited in the GenBank database under accession number MT550884. 93 2.3. Functional cloning of srpA 94 The srpA gene including 257 bp of its upstream region and 89 bp of its downstream region was 95 cloned from the genomic DNA of HNBY78 (accession number PRJNA616172) and then inserted 96 into the shuttle vector pAM401.
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