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A Lack of Drugs for Antibiotic- Resistant Gram-Negative Bacteria

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A Lack of Drugs for Antibiotic- Resistant Gram-Negative Bacteria CORRESPONDENcE LINK TO ORIGINA l A RT I C l E To develop these antibacterial drugs, A lack of drugs for antibiotic- it is necessary to understand the operative mechanism of class C ESBLs to extend their resistant Gram-negative bacteria substrate spectrum. Our kinetic data and crystal structure7 of a plasmid-encoded Jung Hun Lee, Seok Hoon Jeong, Sun-Shin Cha and Sang Hee Lee class C ESBL (that is, CMY-10) clarify this mechanism. The region responsible for the extended substrate spectrum is the Payne et al. recently reported an excellent (for example, cefotaxime and ceftazidime)4. R2-loop (amino-acid residues 289–307)7. overview of a target-based approach to new Most of the known ESBLs are class A and D Our sequence alignment of four class C antibacterial development and the lack of β-lactamases, but recently, several class C ESBLs shows that the R2-loop includes new antibacterial drugs in late-stage develop­ ESBLs were reported in Gram-negative bac- all regions responsible for the extended ment several years ago1. This observation teria: KL5, HD6, CMY-10 (REF. 7) and CMY-19 substrate spectrum in all class C ESBLs, com- (REF. 8) (FIG. 1) has also been made by the participants in . The hydrolytic efficiency (kcat/Km) pared with P99 (a class C non-ESBL) : the recent forum2 of anti-infective research of class C ESBLs for ceftazidime was higher • three amino-acid deletion (residues and development. Also, the Infectious than or similar to that (0.029 µM–1 s–1) 303–305) of CMY-10 (REF. 7); Diseases Society of America recently identi- of SHV-38 (SHV stands for sulphydryl • four amino-acid deletion (residues fied six top-priority dangerous pathogens variable)9, a typical class A ESBL. 293–296) of HD6; — extended-spectrum β-lactamase (ESBL)- Most of the class C β-lactamases have • the single amino-acid substitution producing Enterobacteriaceae, Acinetobacter hydrolysing activity against cephamycins (L296H) of KL5; baumannii, Pseudomonas aeruginosa, vanco- (that is, second-generation cephalosporins: • the single amino-acid substitution mycin-resistant Enterococcus faecium, cefoxitin and cefotetan), which are not (A292S) of CMY-19 (REF. 8). methicillin-resistant Staphylococcus aureus hydrolysed by class A or D ESBLs4–8. These natural mutations in the R2-loop and Aspergillus species — for which there are Cefepime (a fourth-generation oxyimino- can change the architecture of the active few or no drugs in late-stage development. cephalosporin) was also inactivated by KL, site in class C ESBLs, thereby affecting their This could further limit future safe and HD and CMY-19 ESBLs5,6,8. Rubinstein hydrolysing activity. Owing to the deletion effective choices for treating these infections3. and Zhanel have noted that physicians are in CMY-10, for example, the R2-loop in Three of these six pathogens are anti- increasingly being forced to use the carbap- the R2 active site (that is, the region that biotic-resistant Gram-negative bacteria. enems (for example, imipenem or mero- accommodates the R2 side-chain at C3 of Recently, antibacterial drugs against ESBL- penem) and fluoroquinolones (for example, the β-lactam nucleus in oxyimino-cephalo­ producing Gram-negative bacteria accounted ciprofloxacin or levofloxacin) as first-line sporins) displays noticeable structural for ~15% (2 out of 13) of all antibacterial therapy for ESBL-producing Gram-negative alterations. The shortened path of the drugs undergoing development in Phase II bacteria; indeed, the situation will become connection R2-loop between α10 and β11 trials or later clinical studies3. However, there even more severe as ESBL-producing organ- induces the ~2.5 Å shift of α9 and α10 rela- are no drugs being developed against class isms increasingly become concomitantly tive to the adjacent helix α11 in CMY-10 C ESBL-producing Gram-negative bacteria. resistant to the fluoroquinolones2. compared with both P99 (REF. 11) and GC1 Here, we draw attention to important aspects However, we recently found that the (REF. 12) β-lactamases, thereby opening of urgently needed antibacterial drugs against CMY-10 ESBL had higher imipenem- the gap between α9–α10 and α11 (REF. 7). class C ESBL-producing Gram-negative bac- hydrolysing activity than OXA-23, a class D Therefore, the bulky R2 side-chain of oxy- teria, which have been overlooked by these carbapenemase7,10. Gram-negative bacteria imino-cephalosporins could fit snugly into reports. We also suggest that the category of producing such class C ESBLs could present the significant widening of the R2 active site ESBLs should be expanded. a major therapeutic challenge, and so new in this way. ESBLs are a group of enzymes for which antibacterial drugs against class C ESBL- Clinically available β-lactamase inhibi- the substrate spectrum has extended to producing Gram-negative bacteria are tors (for example, clavulanic acid, sulbactam third-generation oxyimino-cephalosporins urgently needed. or tazobactam) co-administered with less Figure 1 | A sequence alignment of amino-acid residues near the H-9 AF357598; PDB code, 1ZKJ); CMY-19 (Klebsiella pneumoniae HKY466; (α9) and H-10 (α10) helix of class C β-lactamases with extended GenBank accession no. AB194410); HD (Serratia marcescens HD; GenBank substrate spectrum. Alignment among CMY-10 and P99 β-lactamases for accession no. AY336102), KL (Escherichia coli KL; GenBank accession no. which structures are available is performed based on their superimposed AY533244); and P99 (Enterobacter cloacae P99; GenBank accession no. structures. The image above the sequence alignment indicates secondary X07274; PDB code, 2BLT) is shown. The R2-loop of residues 289–307 is structure annotation of CMY-10. A partial amino-acid sequence alignment shaded. CMY-10, CMY-19, HD and KL are class C extended-spectrum of CMY-10 (Enterobacter aerogenes K9911729; GenBank accession no. β-lactamases (ESBLs), whereas P99 is a class C non-ESBL. NatUre reviews | DRUG DIScOVERY www.nature.com/reviews/drugdisc © 2007 Nature Publishing Group CORRESPONDENcE Sang Hee Lee is Chair and professor of biological 8. Wachino, J. et al. Horizontal transfer of bla -bearing effective β-lactams are effective against class CMY sciences, Director of Center for Antibiotic Resistance at plasmids among clinical Escherichia coli and Klebsiella A beta-lactamases, but have little or no pneumoniae isolates and emergence of cefepime- Myongji University, San 38-2 Namdong, Yongin, activity against class C β-lactamases. hydrolyzing CMY-19. Antimicrob. Agents Chemother. Gyeonggido 449-728, Republic of Korea. 50, 534–541 (2006). Because Gram-negative bacteria producing Correspondence to S.H.L. 9. Poirel, L. et al. Emergence in Klebsiella pneumoniae of a chromosome-encoded SHV β-lactamase that class C ESBLs are becoming an increasingly e-mail: [email protected] 5–8 compromises the efficacy of imipenem. Antimicrob. common cause of nosocomial infections , Agents Chemother. 47, 755–758 (2003). doi:10.1038/nrd2201-c1 there is an urgent need to develop an 10. Lee, S. H., Jeong, S. H. & Cha, S. S. Screening for carbapenems-resistant Gram-negative bacteria. inhibitor of class C ESBLs or to discover new Lancet Infect. Dis. 6, 682–684 (2006). antibacterial drugs for these class C ESBL- 1. Payne, D. J., Gwynn, M. N., Holmes, D. J. & 11. Lobkovsky, E. et al. Evolution of an enzyme activity: Pompliano, D. L. Drugs for bad bugs: confronting the crystallographic structure at 2 Å resolution of producing clinical isolates. Such efforts challenges of antibacterial discovery. Nature Rev. Drug cephalosporinase from the ampC gene of could be aided considerably by the structural Discov. 6, 29–40 (2007). Enterobacter cloacae P99 and comparison with a 2. Bradley, J. S. et al. Anti-infective research and class A penicillinase. Proc. Natl Acad. Sci. USA 90, information on class C ESBLs highlighted development-problems, challenges, and solutions. 11257–11261 (1993). above13. At present, a few academic research Lancet Infect. Dis. 7, 68–78 (2007). 12. Crichlow, G. V. et al. Structure of the extended- 3. Talbot, G. H. et al. Bad bugs need drugs: an update on spectrum class C β-lactamase of Enterobacter cloacae groups (such as our group and Shoichet’s the development pipeline from the Antimicrobial GC1, a natural mutant with a tandem tripeptide laboratory14) and small pharmaceutical Availability Task Force of the Infectious Diseases insertion. Biochemistry 38, 10256–10261 (1999). 15 Society of America. Clin. Infect. Dis. 42, 657–668 13. Anderson, A. C. The process of structure-based drug companies (for example, Novexel , which (2006). design. Chem. Biol. 10, 787–797 (2003). was spun out of Aventis) are seeking such 4. Paterson, D. L. & Bonomo, R. A. Extended-spectrum 14. Powers, R. A., Morandi, F. & Shoichet, B. K. Structure- β-lactamases: a clinical update. Clin. Microbiol. Rev. based discovery of a novel, noncovalent inhibitor of novel β-lactamase inhibitors. 18, 657–686 (2005). AmpC β-lactamase. Structure 10, 1013–1023 (2002). 5. Mammeri, H. et al. AmpC β-lactamase in an 15. Fox, J. L. The business of developing antibacterials. Jung Hun Lee is a research scientist of Biological Escherichia coli clinical isolate confers resistance to Nature Biotech. 24, 1521–1528 (2006). Sciences at Myongji University, San 38-2 Namdong, expanded-spectrum cephalosporins. Antimicrob. Yongin, Gyeonggido 449-728, Republic of Korea. Agents Chemother. 48, 4050–4053 (2004). Competing interests statement 6. Mammeri, H., Poirel, L., Bemer, P., Drugeon, H. & S.H.L. has received research grants from the National Seok Hoon Jeong is professor of laboratory medicine Nordmann, P. Resistance to cefepime and cefpirome Institute of Health of KCDC in Republic of Korea, the beam- at the College of Medicine, Kosin University, due to a 4-amino-acid deletion in the chromosome- line 6B and 6C of PLS supported by MOST and POSCO, the Serratia marcescens Driving Force Project for the Next Generation of Gyeonggi Busan, Republic of Korea.
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