The influence of natural products upon drug discovery.

Summary: Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

Three Decades of β-Lactamase Inhibitors

The definition of the heterogeneous group of coagulase-negative staphylococci (CoNS) is still based on diagnostic procedures that fulfill the clinical need to differentiate between Staphylococcus aureus and those staphylococci classified historically as being less or nonpathogenic. Due to patient- and procedure-related changes, CoNS now represent one of the major nosocomial pathogens, with S. epidermidis and S. haemolyticus being the most significant species. They account substantially for foreign body-related infections and infections in preterm newborns. While S. saprophyticus has been associated with acute urethritis, S. lugdunensis has a unique status, in some aspects resembling S. aureus in causing infectious endocarditis. In addition to CoNS found as food-associated saprophytes, many other CoNS species colonize the skin and mucous membranes of humans and animals and are less frequently involved in clinically manifested infections. This blurred gradation in terms of pathogenicity is reflected by species- and strain-specific virulence factors and the development of different host-defending strategies. Clearly, CoNS possess fewer virulence properties than S. aureus, with a respectively different disease spectrum. In this regard, host susceptibility is much more important. Therapeutically, CoNS are challenging due to the large proportion of methicillin-resistant strains and increasing numbers of isolates with less susceptibility to glycopeptides.

Coagulase-Negative Staphylococci

2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products.

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

A series of erythromycin A-derived semisynthetic antibiotics, featuring incorporation of a basic nitrogen atom into a ring expanded (15-membered) macrocyclic lactone, have been prepared and biologically evaluated. Semisynthetic modifications focused upon (1) varied substitution at the macrocyclic ring nitrogen and (2) epimerization or amine substitution at the C-4" hydroxyl site within the cladinose sugar. In general, the new azalides exhibit improved Gram-negative potency, expanding the spectrum of erythromycin A to fully include Haemophilus influenzae and Neisseria gonorrhoeae. When compared to erythromycin A, the azalides exhibit substantially increased half-life and area-under-the-curve values in all species studied. The overall in vitro/in vitro performance of N-methyl, C-4" epimers 3a and 9; and C-4" amine 11 identify these compounds as the most interesting erythromycin A-superior agents. Compound 3a has been advanced to clinical study.

Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-AZA-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides.

We report a multicity outbreak of cfr-containing linezolid-resistant Staphylococcus epidermidis in Ohio. Thirty-nine isolates were obtained from 2 hospitals. Two clones with different mechanisms of linezolid resistance were circulating in hospital A. One of these contained the cfr gene, and the other a ribosomal mutation. The clone containing cfr was identical in both hospitals.

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Multicity Outbreak of Linezolid-Resistant Staphylococcus epidermidis Associated with Clonal Spread of a cfr-Containing Strain

More than 90% of community hospital-isolated strains of Staphylococcus (including methicillin-resistant isolates), Streptococcus, Haemophilus, Neisseria, Branhamella, Bacteroides, Escherichia coli, Klebsiella, Enterobacter aerogenes, Proteus, and Acinetobacter calcoaceticus were inhibited by the sulbactam/ampicillin (1:2) combination at concentrations of 8 micrograms/16 micrograms per ml. The peak serum level from a 15-min infusion of 1 g/2 g of sulbactam/ampicillin is more than seven times this 90% end point. Excellent bactericidal activity was demonstrated against ampicillin-resistant isolates. Ampicillin-resistant strains did not develop resistance to sulbactam/ampicillin when they were serially transferred in the presence of sublethal concentrations of the combination. In mice the combination was active against a variety of acute, fatal infections produced by ampicillin-resistant bacterial isolates, including methicillin-resistant strains of Staphylococcus aureus and mixed anaerobes. The in vitro and in vivo properties of sulbactam/ampicillin, coupled with its reliable pharmacokinetic performance, appear to make the combination ideally suited for the treatment of polymicrobial (aerobe-anaerobe) infections.

Sulbactam/ampicillin: in vitro spectrum, potency, and activity in models of acute infection.

ferred in the presence of sublethal concentrations of the combination. In mice the combination was active against a variety of acute, fatal infections produced by ampicillin-resistant bacterial isolates, including methicillin-resistant strains of Staphylococcus aureus and mixed anaerobes. The in vitro and in vivo properties of sulbactam/ampicillin, coupled with its reliable pharmacokinetic performance, appear to make the combination ideally suited for the treatment of polymicrobial (aerobe-anaerobe) infections.

Sulbactam/Ampicillin: In Vitro Spectrum, Potency, and Activity in Models of

A new antibiotic, CJ-17,665 (I) was isolated from the fermentation broth of Aspergillus ochraceus, CL41582. It inhibits growth of multi-drug resistant Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, with MICs of 12.5, 12.5 and 25 microg/ml, respectively. The structure contains a diketopiperazine and an indole N-oxide moiety that is unusual in natural products.

Lori Brennan

Papers

Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-AZA-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides.

Multicity Outbreak of Linezolid-Resistant Staphylococcus epidermidis Associated with Clonal Spread of a cfr-Containing Strain

Sulbactam/ampicillin: in vitro spectrum, potency, and activity in models of acute infection.

Sulbactam/Ampicillin: In Vitro Spectrum, Potency, and Activity in Models of

A new antibiotic CJ-17,665 from Aspergillus ochraceus.