Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing .

Introduction: Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant , particularly those that are carbapenem resistant. CZA resistance in producing PER, a class A extended-spectrum β-lactamase, has been well documented . However, data regarding clinical isolates are scarce.

Mutations in the efflux pump regulator MexZ shift tissue colonization by Pseudomonas aeruginosa to a state of antibiotic tolerance.

Mutations in mexZ, encoding a negative regulator of the expression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics.

A whole-cell hypersensitive biosensor for beta-lactams based on the AmpR-AmpC regulatory circuit from the Antarctic Pseudomonas sp. IB20.

Detecting antibiotic residues is vital to minimize their impact. Yet, existing methods are complex and costly. Biosensors offer an alternative.

Activity of imipenem/relebactam and comparators against KPC-producing Klebsiella pneumoniae and imipenem-resistant Pseudomonas aeruginosa.

Purpose: Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in vitro antimicrobial activity of imipenem/relebactam against a collection of recent clinical isolates of carbapenem-non-susceptible P. aeruginosa and K.

Biosensors for Inducers of Transient Antibiotic Resistance.

The acquisition of an antibiotic resistance phenotype can be due to genetic modifications (heritable) or transient changes in bacterial physiology (non-heritable). Induction of the expression of multidrug efflux pumps by specific compounds/growth conditions is one of the causes of Pseudomonas aeruginosa transient resistance. Biosensor strains have been used for decades to analyze real-time changes in transcription and (less frequently) translation of different genes, in different mutants, growing under several conditions or in the presence of different compounds.

Dynamics of the MRSA Population in a Chilean Hospital: a Phylogenomic Analysis (2000-2016).

The global dissemination of methicillin-resistant Staphylococcus aureus (MRSA) is associated with the emergence and establishment of clones in specific geographic areas. The Chilean-Cordobes clone (ChC) (ST5-SCCI) has been the predominant MRSA clone in Chile since its first description in 1998, despite the report of other emerging MRSA clones in recent years. Here, we characterize the evolutionary history of MRSA from 2000 to 2016 in a Chilean tertiary health care center using phylogenomic analyses.

Heavy Metal Pollution From a Major Earthquake and Tsunami in Chile Is Associated With Geographic Divergence of Clinical Isolates of Methicillin-Resistant in Latin America.

Methicillin-resistant Staphylococcus aureus (MRSA) is a priority pathogen listed by the World Health Organization. The global spread of MRSA is characterized by successive waves of epidemic clones that predominate in specific geographical regions. The acquisition of genes encoding resistance to heavy-metals is thought to be a key feature in the divergence and geographical spread of MRSA.

Role of the multi-drug efflux systems on the baseline susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam in clinical isolates of non-carbapenemase-producing carbapenem-resistant .

Carbapenem-resistant (CRPA) is one of the pathogens that urgently needs new drugs and new alternatives for its control. The primary strategy to combat this bacterium is combining treatments of beta-lactam with a beta-lactamase inhibitor. The most used combinations against are ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T).

Acquisition of resistance to ceftazidime-avibactam during infection treatment in through D179Y mutation in one of two gene copies without losing carbapenem resistance.

Ceftazidime/Avibactam (CAZ/AVI) is frequently used to treat KPC-producing (KPC-PA) and . CAZ/AVI resistance is driven by several mechanisms. In this mainly occurs through alteration of AmpC, porins, and/or efflux pump overexpression, whereas in it frequently occurs through D179Y substitution in the active site of KPC enzyme.

The MexJK Multidrug Efflux Pump Is Not Involved in Acquired or Intrinsic Antibiotic Resistance in , but Modulates the Bacterial Quorum Sensing Response.

Multidrug efflux pumps are critical elements in both intrinsic and acquired antibiotic resistance of bacterial populations. Consequently, most studies regarding these protein machineries focus on this specific phenotype. Nevertheless, different works show that efflux pumps participate in other aspects of bacterial physiology too.

Discovery of inhibitors of Pseudomonas aeruginosa virulence through the search for natural-like compounds with a dual role as inducers and substrates of efflux pumps.

Multidrug efflux pumps are ancient elements encoded in every genome, from bacteria to humans. In bacteria, in addition to antibiotics, efflux pumps extrude a wide range of substrates, including quorum sensing signals, bacterial metabolites, or plant-produced compounds. This indicates that their original functions may differ from their recently acquired role in the extrusion of antibiotics during human infection.

The impaired quorum sensing response of Pseudomonas aeruginosa MexAB-OprM efflux pump overexpressing mutants is not due to non-physiological efflux of 3-oxo-C12-HSL.

Multidrug (MDR) efflux pumps are ancient and conserved molecular machineries with relevant roles in different aspects of the bacterial physiology, besides antibiotic resistance. In the case of the environmental opportunistic pathogen Pseudomonas aeruginosa, it has been shown that overexpression of different efflux pumps is linked to the impairment of the quorum sensing (QS) response. Nevertheless, the causes of such impairment are different for each analysed efflux pump.

Naringenin Inhibition of the Quorum Sensing Response Is Based on Its Time-Dependent Competition With -(3-Oxo-dodecanoyl)-L-homoserine Lactone for LasR Binding.

Bacterial quorum sensing (QS) is a cell-to-cell communication system that governs the expression of a large set of genes involved in bacterial-host interactions, including the production of virulence factors. Conversely, the hosts can produce anti-QS compounds to impair virulence of bacterial pathogens. One of these inhibitors is the plant flavonoid naringenin, which impairs the production of QS-regulated virulence factors.

Novel Inducers of the Expression of Multidrug Efflux Pumps That Trigger Transient Antibiotic Resistance.

The study of the acquisition of antibiotic resistance (AR) has mainly focused on inherited processes, namely, mutations and acquisition of AR genes. However, inducible, noninheritable AR has received less attention, and most information in this field derives from the study of antibiotics as inducers of their associated resistance mechanisms. Less is known about nonantibiotic compounds or situations that can induce AR during infection.

The development of efflux pump inhibitors to treat Gram-negative infections.

One of the possibilities for reducing the emergence and spread of antibiotic resistance is the use of anti-resistance compounds capable of resensitizing resistant microorganisms to current antimicrobials. For this purpose, multidrug efflux pumps, whose inhibition may increase bacterial susceptibility to several antibiotics, including macrolides to which Gram-negatives are considered intrinsically resistant, have emerged as suitable targets. Areas covered: In the current review, the authors discuss different mechanisms that can be exploited for inhibiting multidrug efflux pumps and describe the properties and the potential therapeutic value of already studied efflux pumps inhibitors.

Methods for Measuring the Production of Quorum Sensing Signal Molecules.

One relevant aspect for understanding the bottlenecks that modulate the spread of resistance among bacterial pathogens consists in the effect that the acquisition of resistance may have on the microbial physiology . Whereas studies on the effect of acquiring resistance of bacterial growth are frequently performed, more detailed analyses aiming to understand in depth the cross talk between resistance and virulence, including bacterial communication are less frequent. The bacterial quorum sensing system, is an important intraspecific and interspecific communication system highly relevant for many physiological processes, including virulence and bacterial/host interactions.

Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant Mutants Overexpressing Efflux Pumps.

It is generally assumed that the acquisition of antibiotic resistance is associated with a fitness cost. We have shown that overexpression of the MexEF-OprN efflux pump does not decrease the fitness of a resistant strain compared to its wild-type counterpart. This lack of fitness cost was associated with a metabolic rewiring that includes increased expression of the anaerobic nitrate respiratory chain when cells are growing under fully aerobic conditions.

Multidrug Efflux Pumps at the Crossroad between Antibiotic Resistance and Bacterial Virulence.

Multidrug efflux pumps can be involved in bacterial resistance to antibiotics at different levels. Some efflux pumps are constitutively expressed at low levels and contribute to intrinsic resistance. In addition, their overexpression may allow higher levels of resistance.

Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants.

Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps.