The structures of pluracidomycins, new carbapenem antibiotics.

Tsuji, Naoki; Nagashima, K.; Kobayashi, Masaaki; Terui, Yoshihiro; Matsumoto, Koichí; Kondo, Eiji

doi:10.7164/antibiotics.35.536

“…Thienamycin was the first "carbapenem" and would eventually serve as the parent or model compound for all carbapenems. A series of other carbapenems were also identified (30,92,107,147,149,162,163,172,233); however, the discovery of thienamycin was paramount.…”

Section: In the Beginning…mentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

¹

,

Endimiani

²

,

Taracila

³

et al. 2011

Antimicrob Agents Chemother

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In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as "slow substrates" or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.Carbapenems play a critically important role in our antibiotic armamentarium. Of the many hundreds of different ␤-lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria. As a result, they are often used as "last-line agents" or "antibiotics of last resort" when patients with infections become gravely ill or are suspected of harboring resistant bacteria (23,(174)(175)(176)229). Unfortunately, the recent emergence of multidrug-resistant (MDR) pathogens seriously threatens this class of lifesaving drugs (189). Several recent studies clearly show that resistance to carbapenems is increasing throughout the world (35,64,73,123,151,155,173,200). Despite this menacing trend, our understanding of how to best use these agents is undergoing a renaissance, especially concerning their role with regard to ␤-lactamase inhibition. In this context, we view the number, type, and diversity of carbapenems as compelling reasons to explore these compounds for new insights into drug development.

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“…A wide variety of carbapenem drugs, including asparenomycins (7), carpetimycins (6), olivanic acids (2), pluracidomycins (17), PS-series compounds (11,14,15), and thienamycins (4,5,16), have been derived from strains of Streptomyces spp. Similar antimicrobial agents have also been produced by strains of Serratia and Erwinia spp.…”

mentioning

confidence: 99%

Multicenter in vitro evaluation of SM-7338, a new carbapenem

Jones¹,

Aldridge²,

Allen³

et al. 1989

Antimicrob Agents Chemother

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A new carbapenem, SM-7338, was compared with imipenem, cefotaxime, and ceftazidime at five medical centers. Nearly 6,000 strains were tested by reference methods of the National Committee for Clinical Laboratory Standards, and SM-7338 inhibited the largest percentage of gram-negative bacilli. Its spectrum included all members of the family Enterobacteriaceae (99.7% were susceptible to c4 ,Lg/ml), Pseudomonas spp. (but not Xanthomonas maltophilia), and Acinetobacter spp. The potency and spectrum of SM-7338 against the gram-positive organisms were less than those of imipenem and superior to those of ceftazidime. Only the enterococci and some oxacillin-resistant staphylococci were less susceptible to SM-7338 (MICs for 90% of isolates, .8 ,ug/ml). Organisms resistant to ceftazidime were generally susceptible to SM-7338 and imipenem (76%). However, for one-third of the imipenem.resistant gram-negative bacilli (MICs, >8 ,ug/ml), SM-7338 MICs were -4 ,ug/ml. Some endemic differences in patterns of SM-7338 activity against selected gram-negative species were found among some medical centers.

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“…Subsequently, other structural variations were reported encompassing compounds such as PS-5 (5) (5), carpetimycin A (6) (6), asparenomycin A (7) (7), and pluracidomycin A (8) (8), from a wide variety of streptomycete strains. Following these structures the simplest member of the series, having the completely unsubstituted nucleus, (1, X = CH 2 ), was isolated from bacterial strains of Serratia and Erwinia (9).…”

Section: Carbapenemsmentioning

confidence: 99%

Carbapenems and Penems

Southgate

¹

,

Osborne

²

2000

Kirk-Othmer Encyclopedia of Chemical Technology

2

0

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In the period up to 1970 most β‐lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono‐ and bicyclic β‐lactam structures have been described. The carbapenems originated from natural sources; the penem ring and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are: 7‐oxo‐( R )‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 7 H 7 NO 3 , and 7‐oxo‐( R )‐4‐thia‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 6 H 5 NO 3 S, respectively. Carbapenems include thienamycin (C 11 H 16 N 2 O 4 S), MM 4550 (C 13 H 16 N 2 O 9 S 2 ), MM 13902 (C 13 H 16 N 2 O 8 S 2 ), MM 17880 (C 13 H 18 N 2 O 2 S 2 ), PS‐5 (C 13 H 18 N 2 O 4 S), carpetimycin A (C 14 H 18 N 2 O 6 S), asparenomycin A (C 14 H 16 N 2 O 6 S), and pluracidomycin A (C 9 H 11 NO 10 S 2 ). Only S. cattleya and S. penemfaciens have been reported to give thienamycin. Thienamycin is isolated as a colorless, hygroscopic, zwitterionic solid. Carbapenems are extremely sensitive to many reaction conditions. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure–activity relationships. One consequence of the discovery of the carbapenem natural products has been the development of new synthetic methods. Only chemical synthesis could provide the quantities of N ‐formimidoyl thienamycin (MK 0787) necessary for clinical trials and commercial production. A synthetic approach that involves the [3,4] bond formation using a carbene insertion reaction has been highly successful. A second method makes use of the lactone from acetone dicarboxylate. Thienamycin, the olivanic acids, and the majority of carbapenems are highly active broad‐spectrum antibiotics. Of the natural products, thienamycin is the most potent. Unlike carbapenems, no penems have been found in nature. The penem acid was shown to possess antibacterial activity in spite of its rather limited stability. Penems include SCH 29482 (C 10 H 13 NO 4 S 2 ), SCH 34343 (C 11 H 14 N 2 O 6 S 2 ), FCE 221201 (C 10 H 12 N 2 O 6 S), and others. 6‐Unsubstituted penems exhibit good activity against both gram‐positive and gram‐negative bacteria. Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem–cilastatin combination has become a commercial product. Meropenem was expected to be the second carbapenem on the market.

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The structures of pluracidomycins, new carbapenem antibiotics.

Cited by 35 publications

References 7 publications

Carbapenems: Past, Present, and Future

Carbapenems: Past, Present, and Future

Multicenter in vitro evaluation of SM-7338, a new carbapenem

Carbapenems and Penems

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