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Role of Folp1 and Folp2 Genes in the Action of Sulfamethoxazole and Trimethoprim Against Mycobacteria

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Role of Folp1 and Folp2 Genes in the Action of Sulfamethoxazole and Trimethoprim Against Mycobacteria J. Microbiol. Biotechnol. (2015), 25(9), 1559–1567 http://dx.doi.org/10.4014/jmb.1503.03053 Research Article Review jmb Role of folP1 and folP2 Genes in the Action of Sulfamethoxazole and Trimethoprim Against Mycobacteria Tianzhou Liu1,2, Bangxing Wang2,3, Jintao Guo2, Yang Zhou2, Mugweru Julius2, Moses Njire2, Yuanyuan Cao2,3, Tian Wu2, Zhiyong Liu2, Changwei Wang2, Yong Xu2, and Tianyu Zhang 2* 1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P.R. China 2State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P.R. China 3School of Life Sciences, Anhui University, Hefei, Anhui 230601, P.R. China Received: March 16, 2015 Revised: April 20, 2015 The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) has been shown to be Accepted: April 21, 2015 active against Mycobacterium tuberculosis (Mtb) in clinical tuberculosis (TB) treatment. However, the mechanism of action of TMP-SMX against Mtb is still unknown. To unravel this, First published online we have studied the effect of TMP and SMX by deleting the folP2 gene in Mycobacterium April 23, 2015 smegmatis (Msm), and overexpressing the Mtb and Msm folP1/2 genes in Msm. Knocking out *Corresponding author of the folP2 gene in Msm reduced the minimum inhibitory concentration of SMX 8-fold Phone: +86-18819181735/ compared with wild type. Overexpression of the folP1 genes from Mtb and Msm increased the +86-2032015270; Fax: +86-2032015270; MICs by 4- and 2-fold in Msm for SMX and TMP, respectively. We show a strong correlation E-mail: [email protected]/ between the expression of folP1 and folP2 genes and TMP-SMX resistance in mycobacteria. [email protected] This suggests that a combination of FolP2 inhibitor and SMX could be used for TB treatment pISSN 1017-7825, eISSN 1738-8872 with a better outcome. Copyright© 2015 by The Korean Society for Microbiology Keywords: Mycobacteria, sulfamethoxazole, trimethoprim, folP1, folP2 and Biotechnology Introduction Sulfamethoxazole (SMX) and trimethoprim (TMP) are such potential candidates for TB treatment, having been Tuberculosis (TB) is a chronic disease caused by used in drug regimens for the treatment of various bacterial Mycobacterium tuberculosis (Mtb). The emergence of multidrug infections of the respiratory, urinary, and gastrointestinal resistance (MDR), defined as resistance to at least the two tracts for more than 40 years [1, 10]. TMP and SMX target main first-line anti-TB drugs, rifampicin and isoniazid; successive steps of the folate biosynthesis pathway. SMX extensively drug resistance (XDR), defined as MDR strains inhibits the dihydropteroate synthase (DHPS) activity, that are also resistant to a fluoroquinolone and at least one which catalyzes the addition of dihydropterindiphosphate second-line injectable agent such as amikacin, kanamycin to p-aminobenzoic acid (PABA), a structural analog of (KAN), or capreomycin; and the more severe totally drug SMX. The product of DHPS, 7,8-dihydropteroate (DHP), resistance (TDR), defined as Mtb strains resistant to all reacts with glutamate to form dihydrofolate (DHF), which first- and second-line anti-TB drugs, is an urgent medical is reduced to tetrahydrofolate (THF) by dihydrofolate and public health concern, as the available anti-TB drugs reductase (DHFR), the target of TMP (Fig. 1). Bacteria, exhibit limited efficacy [20, 26]. Development of new drugs fungi, and plants synthesize folate de novo, but mammals is time-consuming, difficult, and expensive. However, if lack DHPS and therefore cannot produce folate. THF is an already existing clinically established effective drugs could essential co-factor involved in the transfer of a one-carbon be used for treatment of TB, then faster and cheaper drug unit and is implicated in the biosynthesis of purines and development coupled with effective TB management would pyrimidines and in the biosynthesis and catabolism of be attained. some amino acids. The combination of TMP and SMX September 2015 ⎪ Vol. 25⎪ No. 9 1560 Liu et al. Fig. 1. SMX and TMP target the folate pathway in mycobacteria. SMX: sulfamethoxazole; TMP: trimethoprim; PABA, p-aminobenzoic acid; DHP: 7,8-dihydropteroate; DHFS: dihydrofolate synthase; DHF: dihydrofolate; THF: tetrahydrofolate; DHFR: dihydrofolate reductase. prevents the emergence of drug resistance and has been that SMX inhibited 80% growth in 117 Mtb clinical isolates demonstrated to be synergistic in many bacteria [3, 10]. at an MIC90 of 9.5 mg/l, regardless of their susceptibility to Vilcheze and Jacobs suggested that the folate biosynthesis the first-line agents. When used in combination with pathway could be a good Mtb target for drug development rifampicin or isoniazid, SMX and TMP have been shown to [19]. be bactericidal and prevent the emergence of drug Forgacs et al. [7] reported that drug-susceptible and resistance in Mtb [11, 19]. Recently, 100 Mtb isolates, drug-resistant Mtb strains were susceptible to TMP/SMX including 48 MDR-TB and 13 XDR-TB, were tested. All the with a bacteriostatic activity of 2/38 µg/ml. Subsequently, isolates had MICs 38 mg/l of SMX, whereas it was less an analysis of 12 drug-susceptible Mtb clinical isolates active inside the macrophages. This implied SMX could be from Australia revealed a susceptibility concentration of a treatment option in selected MDR and XDR TB cases in below 38 µg/ml to SMX [13]. A clinical case study of a patient the initial phase [6]. The analysis of complete genome data infected with an XDR Mtb strain reported susceptibility to revealed the presence of two genes in mycobacteria, folP1 TMP-SMX at 1/19 µg/ml [4]. Huang et al. [9] demonstrated and folP2, which encode proteins that have homology to J. Microbiol. Biotechnol. folP1/2 Gene and Sulfamethoxazole-Trimethoprim in Mycobacteria Treatment 1561 Fig. 2. Comparison of binding mode of SMX in YpDHPS and Mtb FolP1. (A) Crystal structure of the YpDHPS with SMX (green) complex (PDB: 3TZF). (B) Predicted binding mode of SMX (yellow) with Mtb FolP1. PtP in the active site is shown in sticks (grey). Key residues of the binding site are shown as lines and the hydrogen bonds are labeled as red dash lines. respectively, to maintain vector constructs. HYG and KAN DHPS in other bacteria [5, 21]. The overall structure of (Invitrogen) were added at 150 µg/ml and 40 µg/ml, respectively, FolP1 and FolP2 showed a “TIM barrel” fold (n =8, S=8) for Msm when required. SMX and TMP were purchased from with eight α-helices surrounding a central barrel composed Sigma and dissolved in DMSO. of eight parallel β-strands (Fig. 2). The structure and key residues essential for substrate binding of FolP1 and FolP2 Vector Construction of pblMsfp2LRH are highly conserved, with the two proteins sharing only To delete the folP2 gene in Msm, the plasmid pBluescript II about 30% amino acid identity [2, 8, 12]. In mycobacteria, SK(+) was used to construct the vector pblMsfp2LRH. The the folP1 gene is located within the folate operon, whereas upstream 884 bp DNA fragment (ArmL) and the downstream folP2 is organized with genes belonging to fatty acid 982 bp DNA fragment (ArmR) of folP2 were amplified using primers Msfolp2L and Msfolp2R (Table 2), respectively. The two metabolism [5]. It has been shown that the product fragments were cloned into KpnI-EcoRI sites of pBluescript II encoded by the respective folP1 gene exhibited DHPS SK(+) by 3-fragment ligation to form vector pblMSfp2LR, which activity in mycobacteria [12], and folP1 was found to be was verified by restriction digestion and sequencing. The dif-HYG- essential for growth [15]. However, the function of folP2 dif from plasmid pTYdHm [22] was inserted into pblMSfp2LR at has not yet been established. the HindIII site to construct pblMsfp2LRH (Fig. 3). This study thus sets out to explore the role of folP1/ folP2 genes in TMP-SMX resistance in mycobacteria by Construction of the Msm Gene Knockout Mutants gene knockout, overexpression, and drug susceptibility The fragment containing the ArmL–dif-Hyg-dif–ArmR was experiments. excised from vector pblMSfp2LRH at the KpnI and EcoRI sites and transformed into induced Msm-TS53 (Msm containing pJV53Ts) competent cells as previously described [18, 22]. The folP2 gene Materials and Methods was replaced by the Hyg gene through allelic replacement. To remove the Hyg gene, the mutants were cultured into fresh 7H9 Bacterial Strains and Media broth without HYG for 3 days. To remove vector pJV53Ts, the E. coli DH5α was grown at 37°C in Luria Bertani (LB) broth and mutants were cultured into fresh 7H9 broth at 42°C for 3 days, agar. Mycobacterium smegmatis (Msm) mc2155, its mutants, and serially diluted 10-fold and plated onto 7H11 plates containing Mtb H37Rv were grown in Middlebrook 7H9 broth (Difco) 10% sucrose, and incubated at 42°C for 72 h. The loss of the vector supplemented with 10% oleic acid albumin dextrose catalase pJV53Ts in the mutants was subsequently confirmed by plating (OADC) and 0.05% Tween 80, or on solid Middlebrook 7H11 100 colonies in 7H11 plates containing 10% sucrose and KAN or in medium (Difco) supplemented with 10% OADC or containing 10% 7H11 plates containing 10% sucrose at 42°C. sucrose if necessary (Table 1). Hygromycin (HYG; Roche) and Successful folP2 gene deletion was confirmed by PCR using ampicillin (AMP; Sigma) were added at 200 µg/ml and 100 µg/ml, September 2015 ⎪ Vol. 25⎪ No. 9 1562 Liu et al. Table 1. Bacterial strains and plasmids in this study. Source or Strains/plasmids Relevant characteristic(s) reference E. coli DH5α General-purpose cloning strain; F- [ϕ80d lacZ∆M15] ∆D (lacZYA-argF) U169 deoR recA1 [24] endA1 hsdR17 glnV44 thi-1 gyrA96 relA M. smegmatis mc2155 (Msm) Highly transformable derivative of ATCCa 607 [16] Msm-TS53 Msm containing pJV53Ts [22] Msm::p60fp1 Msm containing p60fp1 This study Msm::p60fp2 Msm containing p60fp2 This study Msm::p60Msfp1 Msm containing p60Msfp1 This study Msm::p60Msfp2 Msm containing p60Msfp2 This study Msm∆ folP2 Msm deleted folP2 gene This study Msm∆ folP2-H Msm deleted folP2 gene without Hyg This study Msm∆ folP2-5H Msm deleted folP2 gene without Hyg and pJV53Ts This study M.
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