Antimicrobial Activity and Spectrum of PPI-0903M (T-91825), a Novel Cephalosporin, Tested against a Worldwide Collection of Clinical Strains

Sader, Hélio S.; Fritsche, Thomas R.; Kaniga, Koné; Ge, Yigong; Jones, Ronald N.

doi:10.1128/aac.49.8.3501-3512.2005

Cited by 138 publications

(154 citation statements)

References 15 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…14,15 We have confirmed the antimicrobial activities of CPT and ME with strains from our own collection (Supporting Information), including S. aureus isolates ATCC 29213 (Clinical and Laboratory Standards Institute (CLSI) susceptible standard), vancomycin-resistant MRSA clinical isolates VRS1 and VRS2, and linezolid-resistant MRSA isolates NRS119 and NRS120. Linezolid and vancomycin are commonly used in treatment of MRSA infections, although documented resistance to these agents is worrisome.…”

mentioning

confidence: 80%

Co-opting the Cell Wall in Fighting Methicillin-Resistant Staphylococcus aureus: Potent Inhibition of PBP 2a by Two Anti-MRSA β-Lactam Antibiotics

et al. 2008

View full text Add to dashboard Cite

The second generation of penicillins (including methicillin) was introduced to the clinic in 1959, and by 1961 strains of methicillin-resistant Staphylococcus aureus (MRSA) had emerged. 1 β-Lactam antibiotics were the standard treatment for staphylococcal infections prior to the emergence of MRSA. MRSA is now a global health threat, 2 and community-acquired MRSA has become a significant challenge in the clinic. 2 β-Lactams, which include penicillins, cephalosporins, and carbapenems, target the transpeptidase activity of penicillin-binding proteins (PBPs) involved in cell wall biosynthesis. The molecular basis for resistance to β-lactams in MRSA is complex and a full discussion is outside of the scope of this report; however, the key component is the presence in MRSA isolates of a gene, mecA, absent in methicillin susceptible strains, which encodes a novel PBP (PBP 2a). 3-5 Whereas other S. aureus PBP transpeptidases are susceptible to inhibition by β-lactams, the strains that possess PBP 2a are able to perform the critical cell wall cross-linking reaction even in the presence of β-lactam antibiotics. 3,6,7 PBP 2a escapes inhibition by β-lactams because they fail to readily gain access to the active site of this enzyme.The crystal structure of PBP 2a reveals it to have a closed active site. 8 This is a paradox, as the enzyme must bind to the peptidoglycan to carry out the cross-linking reaction. We previously disclosed that the two strands of peptidoglycan occupy in excess of 1000 Å 3 of volume, 9 hence the X-ray structure does not reveal how peptidoglycan could bind the active site. We presented evidence that interactions of PBP 2a with the peptidoglycan at an allosteric site trigger a conformational change that leads to accessibility to the active site, an event that should play a critical role in the physiological function of this important enzyme. 10,11 In this report we characterize the mode of action of two new anti-MRSA β-lactam antibiotics from Cerexa, Inc., ceftaroline (CPT) a cephalosporin and ME1036 (ME) a carbapenem, which are currently undergoing clinical trials. Both compounds are broad-spectrum antibiotics, but their activities against MRSA and multidrug resistant streptococci are especially noteworthy. In contrast to the commercially available β-lactam antibiotics, CPT and ME are exquisite inhibitors of PBP 2a of MRSA.The backbone of the peptidoglycan is made up of repeating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). A peptide stem-terminating with two D-Ala residues and typically a pentapeptide-is appended to the NAM unit. Compound 1 is a synthetic surrogate for the repeat unit of the peptidoglycan, whose synthesis was reported recently. 12 © 2008 American Chemical Society E-mail: mobashery@nd.edu. The penultimate D-Ala residue of the peptidoglycan acylates an active site serine in PBP 2a resulting in an acyl-enzyme species, with concomitant departure of the terminal D-Ala as the leaving group. This acyl-enzyme species reacts with the second strand of peptidoglycan in the ...

show abstract

mentioning

confidence: 80%

Co-opting the Cell Wall in Fighting Methicillin-Resistant Staphylococcus aureus: Potent Inhibition of PBP 2a by Two Anti-MRSA β-Lactam Antibiotics

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The MIC 90 for 100 strains of hVISA and VISA (19 VISA and 81 hVISA strains) was also 2 g per ml (range, 0.25 to 4 g per ml) (290). A few animal studies have shown ceftaroline to be useful for the treatment of MRSA infections, and in mice, ceftaroline was comparable or superior to vancomycin, linezolid, teicoplanin, and arbekacin (136).…”

Section: Potentially Active Antimicrobials In Developmentmentioning

confidence: 97%

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

et al. 2010

View full text Add to dashboard Cite

SUMMARY The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) over the past decade has provided a challenge to diagnostic microbiologists to detect these strains, clinicians treating patients with infections due to these strains, and researchers attempting to understand the resistance mechanisms. Recent data show that these strains have been detected globally and in many cases are associated with glycopeptide treatment failure; however, more rigorous clinical studies are required to clearly define the contribution of hVISA to glycopeptide treatment outcomes. It is now becoming clear that sequential point mutations in key global regulatory genes contribute to the hVISA and VISA phenotypes, which are associated predominately with cell wall thickening and restricted vancomycin access to its site of activity in the division septum; however, the phenotypic features of these strains can vary because the mutations leading to resistance can vary. Interestingly, changes in the staphylococcal surface and expression of agr are likely to impact host-pathogen interactions in hVISA and VISA infections. Given the subtleties of vancomycin susceptibility testing against S. aureus, it is imperative that diagnostic laboratories use well-standardized methods and have a framework for detecting reduced vancomycin susceptibility in S. aureus.

show abstract

“…Particularly, the prevalence of MRSA (methicillin-resistant Staphylococcus aureus) in hospitals has stimulated the development of more potent carbapenems (ME 1036 [64]) and cephalosporins (PPI 0903M [65]), characterized by very bulky substituents on the bicyclic skeletons. The lethal action of such antibiotics is due to their high affinity for PBP 2a .…”

Section: Discussionmentioning

confidence: 99%

“…Instead of increasing the angular strain and the N1 pyramidality (''twisted amide'') in the azetidinone ring of 1,4-fused bi- [64,65] or tricyclic systems [66], we considered flexible 1,3-bridged bicyclic systems featuring a ''planar amide'' and a large ring susceptible to generate a lot of conformers. Such azetidinones, endowed with a thienamycin-like side-chain at C3 and the related stereochemistry at C3-C5, are readily accessible via a convergent RCM strategy, as illustrated by the synthesis of the 13-membered bicycles E-11 and 12 from the commercial chiron 7, precursor of 10.…”

Section: Discussionmentioning

confidence: 99%

Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

2009

View full text Add to dashboard Cite

a b s t r a c tThe relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a ''planar amide'' instead of the ''twisted amide'' typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C]C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the a-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH.Indeed, bicycles 11 and 12 are modest inhibitors of PBP 2a , while 10 is a good to excellent inhibitor of PBP 2a and R39 bacterial enzymes.

show abstract

Antimicrobial Activity and Spectrum of PPI-0903M (T-91825), a Novel Cephalosporin, Tested against a Worldwide Collection of Clinical Strains

Cited by 138 publications

References 15 publications

Co-opting the Cell Wall in Fighting Methicillin-Resistant Staphylococcus aureus: Potent Inhibition of PBP 2a by Two Anti-MRSA β-Lactam Antibiotics

Co-opting the Cell Wall in Fighting Methicillin-Resistant Staphylococcus aureus: Potent Inhibition of PBP 2a by Two Anti-MRSA β-Lactam Antibiotics

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

Contact Info

Product

Resources

About