The incidence of hospital-acquired infections with multidrug-resistant (MDR) Gram-negative pathogens is increasing at an alarming rate. Equally alarming is the overall lack of efficacious therapeutic options for clinicians, which is due primarily to the acquisition and development of various antibiotic resistance mechanisms that render these drugs ineffective. Among these mechanisms is the reduced permeability of the outer membrane, which prevents many marketed antibiotics from traversing this barrier. To circumvent this, recent drug discovery efforts have focused on conjugating a siderophore moiety to a pharmacologically active compound that has been designed to hijack the bacterial siderophore transport system and trick cells into importing the active drug by recognizing it as a nutritionally beneficial compound. MC-1, a novel siderophore-conjugated ␤-lactam that promotes its own uptake into bacteria, has exquisite activity against many Gram-negative pathogens. While the inclusion of the siderophore was originally designed to facilitate outer membrane penetration into Gram-negative cells, here we show that this structural moiety also renders other clinically relevant antibiotic resistance mechanisms unable to affect MC-1 efficacy. Resistance frequency determinations and subsequent characterization of first-step resistant mutants identified PiuA, a TonB-dependent outer membrane siderophore receptor, as the primary means of MC-1 entry into Pseudomonas aeruginosa. While the MICs of these mutants were increased 32-fold relative to the parental strain in vitro, we show that this resistance phenotype is not relevant in vivo, as alternative siderophore-mediated uptake mechanisms compensated for the loss of PiuA under iron-limiting conditions.

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.

We report a multicity outbreak of cfr-containing linezolid-resistant Staphylococcus epidermidis in Ohio. Thirty-nine isolates were obtained from 2 hospitals. Two clones with different mechanisms of linezolid resistance were circulating in hospital A. One of these contained the cfr gene, and the other a ribosomal mutation. The clone containing cfr was identical in both hospitals.

Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.

We describe the investigation and control of a Klebsiella pneumoniae carbapenemase-producing K. pneumoniae outbreak in a 20-bed surgical intensive care unit during the period from January 1, 2009 through January 1, 2010. Nine patients were either colonized or infected with a monoclonal strain of K. pneumoniae. The implementation of a bundle of interventions on July 2009 successfully controlled the further horizontal spread of this organism.

Increased linezolid utilization preceded the appearance of a linezolid-resistant CoNS clone. Patients probably acquired the clonal strain nosocomially, given the longer time from admission to event among patients with no previous admission to the MD Anderson Cancer Center. Linezolid administration then selected this strain, since all patients received linezolid prior to an event. A linezolid utilization rate of >or=13 defined daily doses/100 patient-days was similar to that reported in two other outbreaks and may be the threshold required to generate an outbreak.

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New antibiotics that are active against multi-drug-resistant strains and difficult-to-treat bacterial infections are needed. Synthetic modification of spectinomycin, a bacterial protein synthesis inhibitor, has been shown to increase antibacterial activity compared with spectinomycin. Aminomethyl spectinomycins are active against Gram-negative and Gram-positive bacterial pathogens. In this study, the ability of aminomethyl spectinomycins to treat biothreat pathogens is examined by MIC profiling, synergy testing, and in vivo efficacy experiments. Compound 1950 exhibited potent antibacterial activity against Gram-negative pathogens Brucella spp., Burkholderia mallei , and Francisella tularensis , but showed little to no growth inhibition against Burkholderia pseudomallei , Bacillus anthracis , and Yersinia pestis . Combination testing in checkerboard assays revealed that aminomethyl spectinomycin-antibiotic combinations had mainly an additive effect against the susceptible biodefense pathogens. The in vivo efficacy of compound 1950 was also demonstrated in mice infected with B. mallei (FMH) or F. tularensis (SchuS4). These results suggest that aminomethyl spectinomycins are promising new candidates for development of therapeutics against biodefense bacterial agents.