Evaluation of penicillin-based inhibitors of the class A and B beta-lactamases from Bacillus anthracis.

Bacillus anthracis contains a class A (Bla1) and class B (Bla2) beta-lactamase, which confer resistance to beta-lactam antibiotics when expressed in Escherichia coli. In an effort to find new beta-lactamase inhibitors, several penicillin derivatives have been evaluated including experimental compounds incorporating a 6-mercaptomethyl group or a 6-pyridylmethylidene group, along with clavulanate and tazobactam, as inhibitors against Bla1 and Bla2. The 6-mercaptomethyl-substituted penicillins showed much greater activity against the zinc-containing Bla2 than Bla1. The compound that incorporated a 6-pyridylmethylidene substituent and a catecholic substituent at the 2' position was the most effective inhibitor of Bla1 with Ki=0.057 microM. Inhibitors containing iron-chelating functional groups have previously been shown to work in combination with antibiotics to inhibit growth of antibiotic-resistant bacteria expressing beta-lactamase. The development of similar compounds, incorporating these types of substituents, may help overcome resistance to currently used antibiotics.

[1]  J. Vaissaire,et al.  Antibiotic Susceptibilities of 96 Isolates of Bacillus anthracis Isolated in France between 1994 and 2000 , 2002, Antimicrobial Agents and Chemotherapy.

[2]  Gianfranco Amicosante,et al.  The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril* , 2003, Journal of Biological Chemistry.

[3]  E. Navas.  Problems associated with potential massive use of antimicrobial agents as prophylaxis or therapy of a bioterrorist attack. , 2002, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[4]  T. G. Bird,et al.  Synthesis and structure-activity relationships of cephalosporins with C-3' catechol-containing residues. , 1992, Journal of Medicinal Chemistry.

[5]  L. Rice,et al.  Inhibitor resistant class A beta-lactamases. , 1999, Frontiers in bioscience : a journal and virtual library.

[6]  H. Dabernat,et al.  First characterization of inhibitor-resistant TEM (IRT) beta-lactamases in Klebsiella pneumoniae strains , 1995, Antimicrobial agents and chemotherapy.

[7]  J. Petrosino,et al.  β-Lactamases: protein evolution in real time , 1998 .

[8]  H. Song,et al.  In-vitro and in-vivo antibacterial activity of LB10517, a novel catechol-substituted cephalosporin with a broad antibacterial spectrum. , 1996, The Journal of antimicrobial chemotherapy.

[9]  Jeremy S. Brown,et al.  Iron acquisition by Gram-positive bacterial pathogens. , 2002, Microbes and infection.

[10]  J. Frère,et al.  Interaction between class B β‐lactamases and suicide substrates of active‐site serine β‐lactamases , 1999 .

[11]  T. Koehler,et al.  Biochemical Characterization of β-Lactamases Bla1 and Bla2 from Bacillus anthracis , 2003, Antimicrobial Agents and Chemotherapy.

[12]  M. Lalitha,et al.  Penicillin resistance in Bacillus anthracis , 1997, The Lancet.

[13]  T. Palzkill,et al.  Molecular analysis of beta-lactamase structure and function. , 2002, International journal of medical microbiology : IJMM.

[14]  P. Petersen,et al.  The synthesis and evaluation of 6-alkylidene-2'β-substituted penam sulfones as β-lactamase inhibitors , 1999 .

[15]  E. Dolence,et al.  Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria , 1992, Antimicrobial Agents and Chemotherapy.

[16]  V. Punda-Polić,et al.  Cutaneous anthrax due to penicillin-resistant Bacillus anthracis transmitted by an insect bite , 1992, The Lancet.

[17]  A. Berg,et al.  Highly antibacterial active aminoacyl penicillin conjugates with acylated bis-catecholate siderophores based on secondary diamino acids and related compounds. , 2002, Journal of medicinal chemistry.

[18]  T. Koehler,et al.  β-Lactamase Genes of the Penicillin-Susceptible Bacillus anthracis Sterne Strain , 2003, Journal of bacteriology.

[19]  R. Levesque,et al.  Molecular basis of antibiotic resistance and beta-lactamase inhibition by mechanism-based inactivators: perspectives and future directions. , 2000, FEMS microbiology reviews.

[20]  J. Frère,et al.  Crystal structure of the IMP-1 metallo beta-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocarboxylate inhibitor: binding determinants of a potent, broad-spectrum inhibitor. , 2000, Biochemistry.

[21]  Youjun Yang,et al.  Class A β-lactamases—enzyme-inhibitor interactions and resistance , 1999 .

[22]  I. Brook,et al.  In vitro resistance of Bacillus anthracis Sterne to doxycycline, macrolides and quinolones. , 2001, International journal of antimicrobial agents.

[23]  D. Payne,et al.  beta-lactamase epidemiology and the utility of established and novel beta-lactamase inhibitors , 2000, Expert opinion on investigational drugs.

[24]  B. Bachmann,et al.  Synthesis and biological activity of 7-alkylidenecephems. , 1995, Journal of medicinal chemistry.