Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure
We propose novel structural requirements that FR259647 derivatives with lower probability of entry into the binding pocket of AmpC β-lactamase are more stable to the enzyme. AmpC β-lactamase is one of the leading causes of Pseudomonas aeruginosa ( P. aeruginosa) resistance to cephalosporins. FR25964...
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| creator | Murano, Kenji Yamanaka, Toshio Toda, Ayako Ohki, Hidenori Okuda, Shinya Kawabata, Kohji Hatano, Kazuo Takeda, Shinobu Akamatsu, Hisashi Itoh, Kenji Misumi, Keiji Inoue, Satoshi Takagi, Tatsuya |
| description | We propose novel structural requirements that FR259647 derivatives with lower probability of entry into the binding pocket of AmpC β-lactamase are more stable to the enzyme.
AmpC β-lactamase is one of the leading causes of
Pseudomonas aeruginosa (
P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC
=
1
μg/mL) against the AmpC β-lactamase overproducing
P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 454;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 455;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 456;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 457] (MIC
=
16
μg/mL) and ceftazidime (CAZ) (MIC
=
128
μg/mL). The stability of FR259647 and FK518 to AmpC β-lactamase was evaluated using MIC assays against both the
P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC β-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC β-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives
4–
9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model. |
| doi_str_mv | 10.1016/j.bmc.2007.11.074 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_70405493</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0968089607010425</els_id><sourcerecordid>70405493</sourcerecordid><originalsourceid>FETCH-LOGICAL-c381t-a7371d9617b0ce86ae164fa483d1bc5cccc374bf91a0805162f21ff69452d9e83</originalsourceid><addsrcrecordid>eNp9kctu1TAQQC0EopfCB7BB3sAuwZM4iS1W1S0vqRILYG05zlj1lROntlOpv8WH8E24uhHsmMXM5sxDZwh5DawGBv37Uz3Opm4YG2qAmg38CTkA73nVthKekgOTvaiYkP0FeZHSiTHWcAnPyQUIJhrO5IH47zluJm9RexrxbnMRZ1xyojZEmm-RpqxH511-oMHSJdyjpwbXW-1DWkN0S6I50Kt5PdLfvyqvTdazTkjHkiYaFtpeV2lfgS_JM6t9wld7vSQ_P338cfxS3Xz7_PV4dVOZVkCu9NAOMMkehpEZFL1G6LnVXLQTjKYzJdqBj1aCZoJ10De2AWt7ybtmkijaS_LuPHeN4W7DlNXskkHv9YJhS2pgnHVctgWEM2hiSCmiVWt0s44PCph6VKxOqihWj4oVgCqKS8-bffg2zjj969idFuDtDuhktLdRL8alv1zDGhCyawr34cxhUXHvMKpkHC4Gp_IEk9UU3H_O-APL5ZsH</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>70405493</pqid></control><display><type>article</type><title>Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><creator>Murano, Kenji ; Yamanaka, Toshio ; Toda, Ayako ; Ohki, Hidenori ; Okuda, Shinya ; Kawabata, Kohji ; Hatano, Kazuo ; Takeda, Shinobu ; Akamatsu, Hisashi ; Itoh, Kenji ; Misumi, Keiji ; Inoue, Satoshi ; Takagi, Tatsuya</creator><creatorcontrib>Murano, Kenji ; Yamanaka, Toshio ; Toda, Ayako ; Ohki, Hidenori ; Okuda, Shinya ; Kawabata, Kohji ; Hatano, Kazuo ; Takeda, Shinobu ; Akamatsu, Hisashi ; Itoh, Kenji ; Misumi, Keiji ; Inoue, Satoshi ; Takagi, Tatsuya</creatorcontrib><description>We propose novel structural requirements that FR259647 derivatives with lower probability of entry into the binding pocket of AmpC β-lactamase are more stable to the enzyme.
AmpC β-lactamase is one of the leading causes of
Pseudomonas aeruginosa (
P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC
=
1
μg/mL) against the AmpC β-lactamase overproducing
P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 454;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 455;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 456;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 457] (MIC
=
16
μg/mL) and ceftazidime (CAZ) (MIC
=
128
μg/mL). The stability of FR259647 and FK518 to AmpC β-lactamase was evaluated using MIC assays against both the
P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC β-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC β-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives
4–
9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2007.11.074</identifier><identifier>PMID: 18082409</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>AmpC β-lactamase ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Bacterial Proteins - antagonists & inhibitors ; Bacterial Proteins - chemistry ; Bacterial Proteins - metabolism ; beta-Lactam Resistance - drug effects ; beta-Lactamase Inhibitors ; beta-Lactamases - chemistry ; beta-Lactamases - metabolism ; Biological and medical sciences ; Cephalosporin ; Cephalosporins - chemistry ; Cephalosporins - pharmacology ; Conformational studies ; Enzyme Stability - drug effects ; Imaging, Three-Dimensional ; Medical sciences ; Models, Molecular ; Molecular Structure ; Pharmacology. Drug treatments ; Protein Binding ; Pseudomonas aeruginosa ; Pseudomonas aeruginosa - drug effects</subject><ispartof>Bioorganic & medicinal chemistry, 2008-03, Vol.16 (5), p.2261-2275</ispartof><rights>2007 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-a7371d9617b0ce86ae164fa483d1bc5cccc374bf91a0805162f21ff69452d9e83</citedby><cites>FETCH-LOGICAL-c381t-a7371d9617b0ce86ae164fa483d1bc5cccc374bf91a0805162f21ff69452d9e83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2007.11.074$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20218952$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18082409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Murano, Kenji</creatorcontrib><creatorcontrib>Yamanaka, Toshio</creatorcontrib><creatorcontrib>Toda, Ayako</creatorcontrib><creatorcontrib>Ohki, Hidenori</creatorcontrib><creatorcontrib>Okuda, Shinya</creatorcontrib><creatorcontrib>Kawabata, Kohji</creatorcontrib><creatorcontrib>Hatano, Kazuo</creatorcontrib><creatorcontrib>Takeda, Shinobu</creatorcontrib><creatorcontrib>Akamatsu, Hisashi</creatorcontrib><creatorcontrib>Itoh, Kenji</creatorcontrib><creatorcontrib>Misumi, Keiji</creatorcontrib><creatorcontrib>Inoue, Satoshi</creatorcontrib><creatorcontrib>Takagi, Tatsuya</creatorcontrib><title>Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>We propose novel structural requirements that FR259647 derivatives with lower probability of entry into the binding pocket of AmpC β-lactamase are more stable to the enzyme.
AmpC β-lactamase is one of the leading causes of
Pseudomonas aeruginosa (
P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC
=
1
μg/mL) against the AmpC β-lactamase overproducing
P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 454;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 455;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 456;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 457] (MIC
=
16
μg/mL) and ceftazidime (CAZ) (MIC
=
128
μg/mL). The stability of FR259647 and FK518 to AmpC β-lactamase was evaluated using MIC assays against both the
P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC β-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC β-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives
4–
9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model.</description><subject>AmpC β-lactamase</subject><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Bacterial Proteins - antagonists & inhibitors</subject><subject>Bacterial Proteins - chemistry</subject><subject>Bacterial Proteins - metabolism</subject><subject>beta-Lactam Resistance - drug effects</subject><subject>beta-Lactamase Inhibitors</subject><subject>beta-Lactamases - chemistry</subject><subject>beta-Lactamases - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cephalosporin</subject><subject>Cephalosporins - chemistry</subject><subject>Cephalosporins - pharmacology</subject><subject>Conformational studies</subject><subject>Enzyme Stability - drug effects</subject><subject>Imaging, Three-Dimensional</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Binding</subject><subject>Pseudomonas aeruginosa</subject><subject>Pseudomonas aeruginosa - drug effects</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctu1TAQQC0EopfCB7BB3sAuwZM4iS1W1S0vqRILYG05zlj1lROntlOpv8WH8E24uhHsmMXM5sxDZwh5DawGBv37Uz3Opm4YG2qAmg38CTkA73nVthKekgOTvaiYkP0FeZHSiTHWcAnPyQUIJhrO5IH47zluJm9RexrxbnMRZ1xyojZEmm-RpqxH511-oMHSJdyjpwbXW-1DWkN0S6I50Kt5PdLfvyqvTdazTkjHkiYaFtpeV2lfgS_JM6t9wld7vSQ_P338cfxS3Xz7_PV4dVOZVkCu9NAOMMkehpEZFL1G6LnVXLQTjKYzJdqBj1aCZoJ10De2AWt7ybtmkijaS_LuPHeN4W7DlNXskkHv9YJhS2pgnHVctgWEM2hiSCmiVWt0s44PCph6VKxOqihWj4oVgCqKS8-bffg2zjj969idFuDtDuhktLdRL8alv1zDGhCyawr34cxhUXHvMKpkHC4Gp_IEk9UU3H_O-APL5ZsH</recordid><startdate>20080301</startdate><enddate>20080301</enddate><creator>Murano, Kenji</creator><creator>Yamanaka, Toshio</creator><creator>Toda, Ayako</creator><creator>Ohki, Hidenori</creator><creator>Okuda, Shinya</creator><creator>Kawabata, Kohji</creator><creator>Hatano, Kazuo</creator><creator>Takeda, Shinobu</creator><creator>Akamatsu, Hisashi</creator><creator>Itoh, Kenji</creator><creator>Misumi, Keiji</creator><creator>Inoue, Satoshi</creator><creator>Takagi, Tatsuya</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20080301</creationdate><title>Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure</title><author>Murano, Kenji ; Yamanaka, Toshio ; Toda, Ayako ; Ohki, Hidenori ; Okuda, Shinya ; Kawabata, Kohji ; Hatano, Kazuo ; Takeda, Shinobu ; Akamatsu, Hisashi ; Itoh, Kenji ; Misumi, Keiji ; Inoue, Satoshi ; Takagi, Tatsuya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-a7371d9617b0ce86ae164fa483d1bc5cccc374bf91a0805162f21ff69452d9e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>AmpC β-lactamase</topic><topic>Antibacterial agents</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Bacterial Proteins - antagonists & inhibitors</topic><topic>Bacterial Proteins - chemistry</topic><topic>Bacterial Proteins - metabolism</topic><topic>beta-Lactam Resistance - drug effects</topic><topic>beta-Lactamase Inhibitors</topic><topic>beta-Lactamases - chemistry</topic><topic>beta-Lactamases - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cephalosporin</topic><topic>Cephalosporins - chemistry</topic><topic>Cephalosporins - pharmacology</topic><topic>Conformational studies</topic><topic>Enzyme Stability - drug effects</topic><topic>Imaging, Three-Dimensional</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Binding</topic><topic>Pseudomonas aeruginosa</topic><topic>Pseudomonas aeruginosa - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murano, Kenji</creatorcontrib><creatorcontrib>Yamanaka, Toshio</creatorcontrib><creatorcontrib>Toda, Ayako</creatorcontrib><creatorcontrib>Ohki, Hidenori</creatorcontrib><creatorcontrib>Okuda, Shinya</creatorcontrib><creatorcontrib>Kawabata, Kohji</creatorcontrib><creatorcontrib>Hatano, Kazuo</creatorcontrib><creatorcontrib>Takeda, Shinobu</creatorcontrib><creatorcontrib>Akamatsu, Hisashi</creatorcontrib><creatorcontrib>Itoh, Kenji</creatorcontrib><creatorcontrib>Misumi, Keiji</creatorcontrib><creatorcontrib>Inoue, Satoshi</creatorcontrib><creatorcontrib>Takagi, Tatsuya</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Murano, Kenji</au><au>Yamanaka, Toshio</au><au>Toda, Ayako</au><au>Ohki, Hidenori</au><au>Okuda, Shinya</au><au>Kawabata, Kohji</au><au>Hatano, Kazuo</au><au>Takeda, Shinobu</au><au>Akamatsu, Hisashi</au><au>Itoh, Kenji</au><au>Misumi, Keiji</au><au>Inoue, Satoshi</au><au>Takagi, Tatsuya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2008-03-01</date><risdate>2008</risdate><volume>16</volume><issue>5</issue><spage>2261</spage><epage>2275</epage><pages>2261-2275</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>We propose novel structural requirements that FR259647 derivatives with lower probability of entry into the binding pocket of AmpC β-lactamase are more stable to the enzyme.
AmpC β-lactamase is one of the leading causes of
Pseudomonas aeruginosa (
P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC
=
1
μg/mL) against the AmpC β-lactamase overproducing
P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 454;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 455;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 456;
Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21–24, 1990, Abs. 457] (MIC
=
16
μg/mL) and ceftazidime (CAZ) (MIC
=
128
μg/mL). The stability of FR259647 and FK518 to AmpC β-lactamase was evaluated using MIC assays against both the
P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC β-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC β-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives
4–
9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>18082409</pmid><doi>10.1016/j.bmc.2007.11.074</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2008-03, Vol.16 (5), p.2261-2275 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | AmpC β-lactamase Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - chemistry Bacterial Proteins - metabolism beta-Lactam Resistance - drug effects beta-Lactamase Inhibitors beta-Lactamases - chemistry beta-Lactamases - metabolism Biological and medical sciences Cephalosporin Cephalosporins - chemistry Cephalosporins - pharmacology Conformational studies Enzyme Stability - drug effects Imaging, Three-Dimensional Medical sciences Models, Molecular Molecular Structure Pharmacology. Drug treatments Protein Binding Pseudomonas aeruginosa Pseudomonas aeruginosa - drug effects |
| title | Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure |
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