Antibiotic resistance in Burkholderia species

Rhodes, Katherine A.; Schweizer, Herbert P.

doi:10.1016/j.drup.2016.07.003

Cited by 253 publications

(226 citation statements)

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“…A critical line of defense against antimicrobial agents in Burkholderia species is the permeability barrier of the outer membrane. Most of these species contain a modified lipopolysaccharide, which results in polymyxin resistance (13). In addition, the permeability of the major outer membrane porin channel Omp38 appears to be low for antibiotics (14).…”

mentioning

confidence: 99%

“…The presence of a large number of multidrug efflux pumps, belonging to the resistance-nodulation-cell division (RND) superfamily, also plays a major role in the intrinsic resistance to a variety of antimicrobials. It has been found that some Bcc bacteria harbor between 11 and 16 hydrophobic/amphiphile efflux 1 (HAE1)-RND pumps that are responsible for drug efflux (13).…”

mentioning

confidence: 99%

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Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN

Kumar

Chou

et al. 2017

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

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Strains of the Burkholderia cepacia complex (Bcc) are Gram-negative opportunisitic bacteria that are capable of causing serious diseases, mainly in immunocompromised individuals. Bcc pathogens are intrinsically resistant to multiple antibiotics, including β-lactams, aminoglycosides, fluoroquinolones, and polymyxins. They are major pathogens in patients with cystic fibrosis (CF) and can cause severe necrotizing pneumonia, which is often fatal. Hopanoid biosynthesis is one of the major mechanisms involved in multiple antimicrobial resistance of Bcc pathogens. The hpnN gene of B. multivorans encodes an integral membrane protein of the HpnN family of transporters, which is responsible for shuttling hopanoids to the outer membrane. Here, we report crystal structures of B. multivorans HpnN, revealing a dimeric molecule with an overall butterfly shape. Each subunit of the transporter contains 12 transmembrane helices and two periplasmic loops that suggest a plausible pathway for substrate transport. Further analyses indicate that HpnN is capable of shuttling hopanoid virulence factors from the outer leaflet of the inner membrane to the periplasm. Taken together, our data suggest that the HpnN transporter is critical for multidrug resistance and cell wall remodeling in Burkholderia.

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confidence: 99%

mentioning

confidence: 99%

Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN

Kumar

Chou

et al. 2017

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

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“…The two most common dangerous species are B cenocepacia and B multivorans . Both have been associated with extreme multidrug resistance, a more rapid decline in lung function and mortality after transplant …”

Section: Discussionmentioning

confidence: 99%

“…One of the most common resistance mechanism seen in Burkholderia species is related to the production of β‐lactamases, including class A β‐lactamases ( Pen A and Pen B), class C β‐lactamases (like Amp C) and class D β‐lactamases. Non β‐lactamase‐mediated resistance, like efflux pumps and reduced outer membrane permeability, also plays a role in the decreased susceptibility of Bcc species toward beta lactam antibiotics . Avibactam is a novel β‐lactamase inhibitor which contrasts the activities of Ambler class A‐serine, C‐serine β‐lactamases and some Ambler class D‐serine enzymes (OXA‐48) to restore the susceptibility to ceftazidime by preventing enzymatic hydrolysis without changing the Class B‐MBL .…”

Section: Introductionmentioning

confidence: 99%

“…Non β-lactamase-mediated resistance, like efflux pumps and reduced outer membrane permeability, also plays a role in the decreased susceptibility of Bcc species toward beta lactam antibiotics. 2 Avibactam is a novel β-lactamase inhibitor which contrasts the activities of Ambler class A-serine, C-serine β-lactamases and some Ambler class D-serine enzymes (OXA-48) to restore the susceptibility to ceftazidime by preventing enzymatic hydrolysis without changing the Class B-MBL. 3 The combination of ceftazidime/ avibactam (CAZ-AVI) represents a novel therapeutic option for Bcc, due to much higher in vitro susceptibility than ceftazidime alone.…”

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Successful ceftazidime‐avibactam treatment of post‐surgery Burkholderia multivorans genomovar II bacteremia and brain abscesses in a young lung transplanted woman with cystic fibrosis

Daccò

Claut

Piconi

et al. 2019

Transplant Infectious Dis

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Burkholderia cepacia complex (Bcc) includes several phenotypically similar but genotypically distinct gram‐negative bacteria (GNB) that can colonize the respiratory tract of Cystic Fibrosis (CF) patients. Pathogens are difficult to treat due to intrinsic resistance to multiple antibiotics and are associated to a more rapid decline in lung function and to increased mortality, particularly after lung transplantation. For all these reasons, chronic infection by Burkholderia (B) cenocepacia is presently considered a relative or absolute contraindication in almost all lung transplant centres. We report the case of a young adult CF patient chronically colonized by B multivorans genomovar II, with diabetes and end‐stage renal disease treated with renal replacement therapy: a few months after lung transplantation, she developed post‐surgery B multivorans bacteremia and multiple brain abscesses. This severe infection did not improve despite multiple standard antibiotic regimen. The introduction of ceftazidime‐avibactam, a new β‐lactam/ β‐lactamase inhibitor combination resulted in clinical recovery and in radiological and biochemical improvement.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Antibiotic resistance in Burkholderia species

Cited by 253 publications

References 123 publications

Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN

Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN

Successful ceftazidime‐avibactam treatment of post‐surgery Burkholderia multivorans genomovar II bacteremia and brain abscesses in a young lung transplanted woman with cystic fibrosis

Medicinal Chemistry of β‐Lactam Antibiotics

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