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Altered penicillin-binding protein 2X (PBP 2X) is a primary beta-lactam antibiotic resistance determinant and is essential to the development of penicillin and cephalosporin resistance in the pneumococcus. We have studied the importance for resistance of 23 amino acid substitutions located in the transpeptidase domain (TD) of PBP 2X from an isolate with high-level resistance, isolate 3191 (penicillin MIC, 16 mug/ml; cefotaxime MIC, 4 microg/ml). Strain R6(2X/2B/1A/mur) (for which the MICs are as described for isolate 3191) was constructed by transforming laboratory strain R6 with all the necessary resistance determinants (altered PBPs 2X, 2B, and 1A and altered MurM) from isolate 3191. Site-directed mutagenesis was used to reverse amino acid substitutions in altered PBP 2X, followed by investigation of the impact of these reversions on resistance levels in R6(2X/2B/1A/mur). Of the 23 substitutions located in the TD of PBP 2X, reversals at six positions decreased the resistance levels in R6(2X/2B/1A/mur). Reversal of the Thr338Pro and Ile371Thr substitutions individually decreased the penicillin and cefotaxime MICs to 2 and 1 microg/ml, respectively, and individually displayed the greatest impact on resistance. To a lesser extent, reversal of the Leu364Phe, Ala369Val, Arg384Gly, and Tyr595Phe substitutions individually also decreased the penicillin and cefotaxime MICs. Reversal at all six positions collectively decreased both the penicillin and the cefotaxime MICs of R6(2X/2B/1A/mur) to 0.06 microg/ml. This study confirms the essential role of altered PBP 2X as a resistance determinant. Our data reveal that, for isolate 3191, the six amino acid substitutions described above are collectively essential to the production of an altered PBP 2X required for high-level resistance to penicillin and cefotaxime.

Titel:	Amino acid mutations essential to production of an altered PBP 2X conferring high-level beta-lactam resistance in a clinical isolate of Streptococcus pneumoniae.
Autor/in / Beteiligte Person:	Smith, AM ; Klugman, KP
Zeitschrift:	Antimicrobial agents and chemotherapy, Jg. 49 (2005-11-01), Heft 11, S. 4622-7
Veröffentlichung:	Washington, American Society for Microbiology, 2005
Medientyp:	academicJournal
ISSN:	0066-4804 (print)
DOI:	10.1128/AAC.49.11.4622-4627.2005
Schlagwort:	Amino Acid Sequence Amino Acid Substitution Humans Microbial Sensitivity Tests Molecular Sequence Data Penicillin-Binding Proteins chemistry Penicillin-Binding Proteins physiology Streptococcus pneumoniae genetics Mutation Penicillin-Binding Proteins genetics Streptococcus pneumoniae drug effects beta-Lactam Resistance
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Antimicrob Agents Chemother] 2005 Nov; Vol. 49 (11), pp. 4622-7. MeSH Terms: Mutation* ; beta-Lactam Resistance* ; Penicillin-Binding Proteins / genetics ; Streptococcus pneumoniae / drug effects ; Amino Acid Sequence ; Amino Acid Substitution ; Humans ; Microbial Sensitivity Tests ; Molecular Sequence Data ; Penicillin-Binding Proteins / chemistry ; Penicillin-Binding Proteins / physiology ; Streptococcus pneumoniae / genetics References: J Antimicrob Chemother. 1990 Jul;26(1):21-8. (PMID: 2211443) ; Antimicrob Agents Chemother. 1980 Mar;17(3):364-71. (PMID: 7425601) ; Mol Microbiol. 1991 Aug;5(8):1993-2002. (PMID: 1766375) ; EMBO J. 1992 Nov;11(11):3831-6. (PMID: 1396576) ; Mol Microbiol. 1992 Sep;6(17):2461-5. (PMID: 1406283) ; FEMS Microbiol Lett. 1993 Jan 15;106(2):171-5. (PMID: 8454182) ; Antimicrob Agents Chemother. 1993 Sep;37(9):1938-44. (PMID: 8239609) ; FEMS Microbiol Lett. 1995 Mar 1;126(3):299-303. (PMID: 7729674) ; Antimicrob Agents Chemother. 1995 Jun;39(6):1306-13. (PMID: 7574521) ; Antimicrob Agents Chemother. 1980 Mar;17(3):434-42. (PMID: 6903436) ; Proc Natl Acad Sci U S A. 1989 Nov;86(22):8842-6. (PMID: 2813426) ; Antimicrob Agents Chemother. 1996 Jan;40(1):152-6. (PMID: 8787897) ; Antimicrob Agents Chemother. 1997 May;41(5):936-42. (PMID: 9145848) ; Microb Drug Resist. 1996 Summer;2(2):177-81. (PMID: 9158756) ; Microb Drug Resist. 1996 Summer;2(2):183-6. (PMID: 9158757) ; J Bacteriol. 1998 Apr;180(7):1831-40. (PMID: 9537382) ; Antimicrob Agents Chemother. 1998 Jun;42(6):1329-33. (PMID: 9624469) ; Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13403-6. (PMID: 9811812) ; Microbiology. 1998 Nov;144 ( Pt 11):3069-78. (PMID: 9846742) ; J Biol Chem. 1999 Jul 2;274(27):19175-80. (PMID: 10383423) ; Antimicrob Agents Chemother. 2005 May;49(5):2002-7. (PMID: 15855525) ; Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4891-6. (PMID: 10759563) ; J Mol Biol. 2000 Jun 2;299(2):477-85. (PMID: 10860753) ; FEMS Microbiol Lett. 2000 Jul 1;188(1):81-5. (PMID: 10867238) ; Microb Drug Resist. 2000 Summer;6(2):105-10. (PMID: 10990264) ; Antimicrob Agents Chemother. 2001 Aug;45(8):2393-6. (PMID: 11451707) ; J Biol Chem. 2003 Nov 7;278(45):44448-56. (PMID: 12923202) ; J Microbiol Methods. 2003 Dec;55(3):807-11. (PMID: 14607425) ; Mol Microbiol. 2003 Nov;50(3):845-55. (PMID: 14617146) ; J Bacteriol. 1991 Nov;173(21):6986-90. (PMID: 1938899) Grant Information: United Kingdom WT_ Wellcome Trust Substance Nomenclature: 0 (Penicillin-Binding Proteins) ; 128284-03-7 (PBP 2x protein, Streptococcus) Entry Date(s): Date Created: 20051028 Date Completed: 20060118 Latest Revision: 20230426 Update Code: 20231215 PubMed Central ID: PMC1280142

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Amino acid mutations essential to production of an altered PBP 2X conferring high-level beta-lactam resistance in a clinical isolate of Streptococcus pneumoniae.