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β-Lactam Resistance Response Triggered by Inactivation of a Nonessential Penicillin-Binding Protein

Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud Palma de Mallorca, Spain.
PLoS Pathogens (Impact Factor: 8.06). 04/2009; 5(3):e1000353. DOI: 10.1371/journal.ppat.1000353
Source: PubMed

ABSTRACT It has long been recognized that the modification of penicillin-binding proteins (PBPs) to reduce their affinity for beta-lactams is an important mechanism (target modification) by which Gram-positive cocci acquire antibiotic resistance. Among Gram-negative rods (GNR), however, this mechanism has been considered unusual, and restricted to clinically irrelevant laboratory mutants for most species. Using as a model Pseudomonas aeruginosa, high up on the list of pathogens causing life-threatening infections in hospitalized patients worldwide, we show that PBPs may also play a major role in beta-lactam resistance in GNR, but through a totally distinct mechanism. Through a detailed genetic investigation, including whole-genome analysis approaches, we demonstrate that high-level (clinical) beta-lactam resistance in vitro, in vivo, and in the clinical setting is driven by the inactivation of the dacB-encoded nonessential PBP4, which behaves as a trap target for beta-lactams. The inactivation of this PBP is shown to determine a highly efficient and complex beta-lactam resistance response, triggering overproduction of the chromosomal beta-lactamase AmpC and the specific activation of the CreBC (BlrAB) two-component regulator, which in turn plays a major role in resistance. These findings are a major step forward in our understanding of beta-lactam resistance biology, and, more importantly, they open up new perspectives on potential antibiotic targets for the treatment of infectious diseases.

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Available from: Andreas Dötsch, Jul 09, 2014
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    • "P. aeruginosa is a highly adaptable microorganism and can develop resistance to different antibiotics. Multidrug-resistance (MDR) strains of P. aeruginosa use different mechanisms for developing resistance such as producing enzymes for inactivating β-lactams like ESBL (extended spectrum beta lactamase), MBL (metallo-β-lactamase) [10], [11], and biofilm formation can enhance ability of resistance in P. aeruginosa [12]. P. aeruginosa isolated from respiratory tract with typical non-mucoid phenotype, but in prolonged infection, can shift to mucoid form with producing large amounts of exopolysaccharide called alginate [13], [14]. "
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    08/2014; 9(2):Doc13. DOI:10.3205/dgkh000233
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    • "These observations suggest that AmpC is the major resistance determinant and MexAB pump by itself is not enough to confer b-lactam resistance. Resistance to b-lactams is also regulated by the CreBCD system (Moya et al., 2009; Zamorano et al., 2010). CreBC forms a two-component system that positively regulates expression of an inner membrane protein CreD (Avison et al., 2001); together, they regulate b-lactam resistance (Avison et al., 2004). "
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    Pathogens and Disease 07/2014; DOI:10.1111/2049-632X.12208 · 2.55 Impact Factor
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    • "The mexABoprM operon is constitutively expressed in wild-type cells under usual laboratory conditions, where the operon contributes to P. aeruginosa's intrinsic resistance to most β-lactams (except for imipenem) and many other antimicrobial agents, including quinolones, tetracycline, chloramphenicol, and macrolides (Morita et al., 2001). Blocking of dacB-encoded non-essential PBP4 determines a highly efficient and complex β-lactam resistance response, triggering the overproduction of AmpC and the specific activation of the CreAB (BlrAB) two-component regulator (Moya et al., 2009). Carbapenems are an important class of anti-pseudomonal βlactams . "
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