A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

We develop approximation algorithms for the problem of placing replicated data in arbitrary networks, where the nodes may both issue requests for data objects and have capacity for storing data objects so as to minimize the average data-access cost. We introduce the data placement problem to model this problem. We have a set of caches F , a set of clients D, and a set of data objects O. Each cache i can store at most u i data objects. Each client j ∈ D has demand d j for a specific data object o(j) ∈ O and has to be assigned to a cache that stores that object. Storing an object o in cache i incurs a storage cost of f o i , and assigning client j to cache i incurs an access cost of d j c ij . The goal is to find a placement of the data objects to caches respecting the capacity constraints, and an assignment of clients to caches so as to minimize the total storage and client access costs. We present a 10-approximation algorithm for this problem. Our algorithm is based on rounding an optimal solution to a natural linear-programming relaxation of the problem. One of the main technical challenges encountered during rounding is to preserve the cache capacities while incurring only a constant-factor increase in the solution cost. We also introduce the connected data placement problem to capture settings where write-requests are also issued for data objects, so that one requires a mechanism to maintain consistency of data. We model this by requiring that all caches containing a given object be connected by a Steiner tree to a root for that object, which issues a multicast message upon a write to (any copy of) that object. The total cost now includes the cost of these Steiner trees. We devise a 14-approximation algorithm for this problem. We show that our algorithms can be adapted to handle two variants of the problem: (a) a k-median variant, where there is a specified bound on the number of caches that may contain a given object, and (b) a generalization where objects have lengths and the total length of the objects stored in any cache must not exceed its capacity.

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An ad hoc wireless network, or simply an ad hoc network, consists of a collection of geographically distributed nodes that communicate with one other over a wireless medium. An ad hoc network differs from cellular networks in that there is no wired infrastructure and the communication capabilities of the network are limited by the battery power of the network nodes. One of the original motivations for ad hoc networks is found in military applications. A classic example of ad hoc networking is network of war fighters and their mobile platforms in battlefields. Indeed, a wealth of early research in the area involved the development of packet-radio networks (PRNs) and survivable radio networks [16]. While military applications still dominate the research needs in ad hoc networking, the recent rapid advent of mobile telephony and plethora of personal digital assistants has brought to the fore a number of potential commercial applications of ad hoc networks. Examples are disaster relief, conferencing, home networking, sensor networks, personal area networks, and embedded computing applications [37].The lack of a fixed infrastructure in ad hoc networks implies that any computation on the network needs to be carried out in a decentralized manner. Thus, many of the important problems in ad hoc networking can be formulated as problems in distributed computing. However, there are certain characteristics of ad hoc networks that makes this study somewhat different than traditional work in distributed computing. In this article, we review some of the characteristic features of ad hoc networks, formulate problems and survey research work done in the area. We focus on two basic problem domains: topology control, the problem of computing and maintaining a connected topology among the network nodes, and routing. This article is not intended to be a comprehensive survey on ad hoc networking. The choice of the problems discussed in this article are somewhat biased by the research interests of the author.The remainder of this article is organized as follows. In Section 2, we describe various aspects relevant to modeling ad hoc networks. In Section 3, we discuss topology control. Since the nodes of an ad hoc network are often associated with points in 2-dimensional space, topology control is closely tied to computational geometry; we will briefly review this relationship and extant work in the area. In Section 4, we discuss routing protocols for ad hoc networks. After a brief overview of the many protocols that have been proposed, we discuss alternative approaches based on the adversarial network model.

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The dominating set problem asks for a small subset D of nodes in a graph such that every node is either in D or adjacent to a node in D. This problem arises in a number of distributed network applications, where it is important to locate a small number of centers in the network such that every node is nearby at least one center. Finding a dominating set of minimum size is NP-complete, and the best known approximation is logarithmic in the maximum degree of the graph and is provided by the same simple greedy approach that gives the well-known logarithmic approximation result for the closely related set cover problem.We describe and analyze new randomized distributed algorithms for the dominating set problem that run in polylogarithmic time, independent of the diameter of the network, and that return a dominating set of size within a logarithmic factor from optimal, with high probability. In particular, our best algorithm runs in O(log n log ∆) rounds with high probability, where n is the number of nodes, ∆ is one plus the maximum degree of any node, and each round involves a constant number of message exchanges among any two neighbors; the size of the dominating set obtained is within O(log ∆) of the optimal in expectation and within O(log n) of the optimal with high probability. We also describe generalizations to the weighted case and the case of multiple covering requirements.

Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA) and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2ΔtarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z’-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the anti-staphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans – S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host.