Approaches to the simultaneous inactivation of metallo- and serine-β-lactamases

Ganta, Sudhakar; Perumal, Senthil K.; Pagadala, Sundar Ram Reddy; Samuelsen, Ørjan; Spencer, James; Pratt, Robertson; Buynak, John D.

doi:10.1016/j.bmcl.2009.02.018

Cited by 30 publications

(21 citation statements)

References 25 publications

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“…The biggest challenges are the metallo-␤-lactamases. However, some progress has been made in identifying potential inhibitors (cephalosporin-derived reverse hydroxamates and oximes, phthalic acid derivatives, mitoxantrone, 4-chloromercuribenzoic acid, sulfonyl-triazole analogs, and NH-1,2,3-triazole-based compounds) (66,84,138,202,248). Alternative inhibitors can include carbapenems with different stereochemistries.…”

Section: Discussionmentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,178

962

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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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Section: Discussionmentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,178

962

View full text Add to dashboard Cite

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“…12) (PDB 2P9V) (450). TEM-2 and OXA-1 ␤-lactamases were also inhibited by O-aryloxycarbonyl hydroxamates, and the MBL GIM-1 was inhibited by a "reverse" hydroxamate (hydroxylamino replacing hydroxylamine) conjugated to a cephalosporin nucleus (131,330). Additional mechanistic studies of hydroxamates and their derivatives, as well as in vitro activity data, will be of much interest.…”

Section: Non-␤-lactam Inhibitorsmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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SUMMARYSince 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 seriousEnterobacteriaceaeand 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.

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“…Among them single molecules as mercaptomethylpenicillinates (Buynak et al, 2004) or reverse hydroxamates and oximes (Ganta et al, 2009) are under development as well as combinations of compounds as BAL30376, which is a mixture of BAL19764, a siderophore monobactam active to class B MBLs, BAL29880, a bridged monobactam active to class C β-lactamases, and clavulanate (Livermore et al, 2010; Page et al, 2011). …”

Section: Inhibitors Of Resistance Determinantsmentioning

confidence: 99%

The intrinsic resistome of bacterial pathogens

Olivares¹,

Bernardini²,

et al. 2013

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Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.

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Approaches to the simultaneous inactivation of metallo- and serine-β-lactamases

Cited by 30 publications

References 25 publications

Carbapenems: Past, Present, and Future

Carbapenems: Past, Present, and Future

Three Decades of β-Lactamase Inhibitors

The intrinsic resistome of bacterial pathogens

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