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Jensen, Susan E.; Paradkar, Ashish S.

doi:10.1023/a:1001755724055

Cited by 66 publications

(28 citation statements)

References 33 publications

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“…1) is a natural inhibitor of ␤-lactamases (enzymes that confer resistance to ␤-lactam antibiotics in many microorganims). The genetics and biochemistry of its production have been intensively studied in Streptomyces clavuligerus for Ͼ25 years (16). This actinomycete also produces several other ␤-lactam compounds, including a number of structurally related clavams (2) (Fig.…”

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confidence: 99%

“…1) (along with other biologically active intermediates on its biosynthetic pathway), which inhibits the transpeptidation reaction in cell wall biosynthesis. The early steps of clavulanic acid and clavam biosynthesis are common, but the pathways to these two structurally related metabolites diverge at clavaminic acid (16). In contrast, cephamycin is biosynthesized by a pathway that is mechanistically distinct from that for the clavams and clavulanic acid (16,17).…”

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“…The early steps of clavulanic acid and clavam biosynthesis are common, but the pathways to these two structurally related metabolites diverge at clavaminic acid (16). In contrast, cephamycin is biosynthesized by a pathway that is mechanistically distinct from that for the clavams and clavulanic acid (16,17). Combinations of ␤-lactam antibiotics and ␤-lactamase inhibitors are well known to be effective against ␤-lactam-resistant bacteria in comparison with ␤-lactams antibiotics alone.…”

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“…Closer inspection of metabolite production patterns among other producers of clavulanic acid, clavams, and cephamycin C, however, suggests that a strong selective pressure, rather than mere chance, has created actinomycetes that coproduce clavulanic acid and a ␤-lactam antibiotic such as cephamycin C. Thus, S. clavuligerus, Streptomyces jumonjinensis, Streptomyces katsurahamanus, and an unclassified Streptomyces sp. all produce clavulanic acid (16). Strikingly, all of these streptomycetes also produce cephamycin C (16).…”

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Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Challis

Hopwood

2003

Proc. Natl. Acad. Sci. U.S.A.

540

398

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In this article we briefly review theories about the ecological roles of microbial secondary metabolites and discuss the prevalence of multiple secondary metabolite production by strains of Streptomyces, highlighting results from analysis of the recently sequenced Streptomyces coelicolor and Streptomyces avermitilis genomes. We address this question: Why is multiple secondary metabolite production in Streptomyces species so commonplace? We argue that synergy or contingency in the action of individual metabolites against biological competitors may, in some cases, be a powerful driving force for the evolution of multiple secondary metabolite production. This argument is illustrated with examples of the coproduction of synergistically acting antibiotics and contingently acting siderophores: two well-known classes of secondary metabolite. We focus, in particular, on the coproduction of ␤-lactam antibiotics and ␤-lactamase inhibitors, the coproduction of type A and type B streptogramins, and the coregulated production and independent uptake of structurally distinct siderophores by species of Streptomyces. Possible mechanisms for the evolution of multiple synergistic and contingent metabolite production in Streptomyces species are discussed. It is concluded that the production by Streptomyces species of two or more secondary metabolites that act synergistically or contingently against biological competitors may be far more common than has previously been recognized, and that synergy and contingency may be common driving forces for the evolution of multiple secondary metabolite production by these sessile saprophytes.

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Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Challis

Hopwood

2003

Proc. Natl. Acad. Sci. U.S.A.

540

398

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“…3 and 4). Clavulanic acid is of increasing clinical importance for its ability to overcome bacterial resistance to penicillins and cephalosporins (5,6) by inactivating ␤-lactamase enzymes (7). AS-Bs convert aspartic acid to asparagine (ref.…”

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The catalytic cycle of β-lactam synthetase observed by x-ray crystallographic snapshots

Miller

Bachmann

Townsend

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The catalytic cycle of the ATP͞Mg 2؉ -dependent enzyme ␤-lactam synthetase (␤-LS) from Streptomyces clavuligerus has been observed through a series of x-ray crystallographic snapshots. Chemistry is initiated by the ordered binding of ATP͞Mg 2؉ and N 2 -(carboxyethyl)-L-arginine (CEA) to the apoenzyme. The apo and ATP͞Mg 2؉ structures described here, along with the previously described CEA⅐␣,␤-methyleneadenosine 5 -triphosphate (CEA⅐AMP-CPP)͞Mg 2؉ structure, illuminate changes in active site geometry that favor adenylation. In addition, an acyladenylate intermediate has been trapped. The substrate analog N 2 -(carboxymethyl)-L-arginine (CMA) was adenylated by ATP in the crystal and represents a close structural analog of the previously proposed CEA-adenylate intermediate. Finally, the structure of the ternary product complex deoxyguanidinoproclavaminic acid (DGPC)⅐AMP͞PP i͞Mg 2؉ has been determined. The CMA-AMP͞PP i͞Mg 2؉ and DGPC⅐AMP͞PPi͞Mg 2؉ structures reveal interactions in the active site that facilitate ␤-lactam formation. All of the ATP-bound structures differ from the previously described CEA⅐AMP-CPP͞Mg 2؉ structure in that two Mg 2؉ ions are found in the active sites. These Mg 2؉ ions play critical roles in both the adenylation and ␤-lactamization reactions.

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Natural Products and Drug Discovery

Demain

Zhang

Natural Products

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SummaryFor more than 50 yr, natural products have served us well in combating infectious bacteria and fungi. During the 20th century, microbial and plant secondary metabolites helped to double our life span, reduced pain and suffering, and revolutionized medicine. The increased development of resistance to older antibacterial, antifungal, and antitumor drugs has been challenged by (1) newly discovered antibiotics (e.g., candins, epothilones); (2) new semisynthetic versions of old antibiotics (e.g., ketolides, glycylcyclines); (3) older underutilized antibiotics (e.g., teicoplainin); and (4) new derivatives of previously undeveloped narrow-spectrum antibiotics (e.g., streptogramins). In addition, many antibiotics are used commercially, or are potentially useful in medicine for purposes other than their antimicrobial action. They are used as antitumor agents, enzyme inhibitors including powerful hypocholesterolemic agents, immunosuppressive agents, antimigraine agents, and so on. A number of these products were first discovered as antibiotics that failed in their development as such, or as mycotoxins.It is unfortunate that the pharmaceutical industry has downgraded natural products just at the time that new assays are available and major improvements have been made in detection, characterization, and purification of small molecules. With the advent of combinatorial biosynthesis, thousands of new des4oeatives can now be made by a biological technique complementary to combinatorial chemistry. Furthermore, only a minor proportion of bacteria and fungi, i.e., 0.1-5%, have thus far been examined for secondary metabolite production. New methods are being developed to cultivate the so-called unculturable microbes from the soil and the sea. High-throughput screening (HTS) of combinatorial chemicals has not provided the numbers of high-quality leads that were anticipated. It has virtually eliminated the most unique source of chemical diversity, i.e., natural products, from the playing field, in favor of combinatorial chemistry. Combinatorial chemistry mainly yields minor modifications of present-day drugs and absolutely requires new scaffolds on which to build. Although comparative genomics is capable of disclosing new targets for drugs, the number of targets is so large that it requires tremendous investments of time and money to set up all the screens necessary to exploit this resource. This can be handled only by HTS methodology, which demands libraries of millions of chemical entities. Although such targets would be excellent for screening natural products, the industry has failed to exploit this unique opportunity and has opted to save funds by eliminating natural-product departments or decreasing their relevance in the hunt for new drugs. It is clear that the future success of the pharmaceutical industry depends on the combining of complementary technologies such as natural product discovery, HTS, integrative and systems biology, combinatorial biosynthesis, and combinatorial chemistry.

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Cited by 66 publications

References 33 publications

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

The catalytic cycle of β-lactam synthetase observed by x-ray crystallographic snapshots

Natural Products and Drug Discovery

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