Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.

Antibiotics and Bacterial Resistance in the 21st Century

Actinomycetes: still a source of novel antibiotics

A wide range of unregulated chemicals of synthetic origin or derived from natural sources, which may be a contender for future regulations are called Emerging Contaminants (ECs). The concentration of ECs ranges from ng/L to μg/L, which is comparatively smaller as compared to other pollutants present in water and wastewater. Even though the environmental concentration is low, ECs still possess a great threat to the humans and ecosystem. These compounds are being widely studied due to their potential health effects, pervasive nature, and difficult degradation through conventional techniques. Pharmaceutical active compounds (PhACs) or pharmaceutical contaminants (PCs) are one of the major groups of ECs which can cause inimical effect on living organisms even at very lower concentration. These contaminants don't degrade easily and persistent for longer periods in the environment due to their stable structure. With the increase in demand of Pharmaceuticals and Personal Care Products (PPCPs), there has been a sharp increase of these pollutants in water bodies. This is mainly due to the inefficiency of conventional wastewater treatment plants in treatment and removal of these PhACs. The proper identification of pharmaceutical groups and development of removal techniques is crucial in the recent times. This review represents a comprehensive summary on PCs, various groups of PCs and an overview of approaches and treatment systems available for their removal. Efficient and effective treatment methods can be useful for completely eradicating these compounds and making the water bodies safe for use. So, the investment of capital and time on research on PCs and their removal techniques can be beneficial for the future. 

Pharmaceutical wastewater as Emerging Contaminants (EC): Treatment technologies, impact on environment and human health

Clostridium difficile epidemiology has changed in recent years, with the emergence of highly virulent types associated with severe infections, high rates of recurrences and mortality. Antibiotic resistance plays an important role in driving these epidemiological changes and the emergence of new types. While clindamycin resistance was driving historical endemic types, new types are associated with resistance to fluoroquinolones. Furthermore, resistance to multiple antibiotics is a common feature of the newly emergent strains and, in general, of many epidemic isolates. A reduced susceptibility to antibiotics used for C. difficile infection (CDI) treatment, in particular to metronidazole, has recently been described in several studies. Furthermore, an increased number of strains show resistance to rifamycins, used for the treatment of relapsing CDI. Several mechanisms of resistance have been identified in C. difficile, including acquisition of genetic elements and alterations of the antibiotic target sites. The C. difficile genome contains a plethora of mobile genetic elements, many of them involved in antibiotic resistance. Transfer of genetic elements among C. difficile strains or between C. difficile and other bacterial species can occur through different mechanisms that facilitate their spread. Investigations of the fitness cost in C. difficile indicate that both genetic elements and mutations in the molecular targets of antibiotics can be maintained regardless of the burden imposed on fitness, suggesting that resistances may persist in the C. difficile population also in absence of antibiotic selective pressure. The rapid evolution of antibiotic resistance and its composite nature complicate strategies in the treatment and prevention of CDI. The rapid identification of new phenotypic and genotypic traits, the implementation of effective antimicrobial stewardship and infection control programs, and the development of alternative therapies are needed to prevent and contain the spread of resistance and to ensure an efficacious therapy for CDI.

https://journals.sagepub.com/doi/pdf/10.1177/2049936115622891

Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection.

Using single-molecule fluorescence resonance energy transfer, we have defined bacterial RNA polymerase (RNAP) clamp conformation at each step in transcription initiation and elongation. We find that the clamp predominantly is open in free RNAP and early intermediates in transcription initiation but closes upon formation of a catalytically competent transcription initiation complex and remains closed during initial transcription and transcription elongation. We show that four RNAP inhibitors interfere with clamp opening. We propose that clamp opening allows DNA to be loaded into and unwound in the RNAP active-center cleft, that DNA loading and unwinding trigger clamp closure, and that clamp closure accounts for the high stability of initiation complexes and the high stability and processivity of elongation complexes.

/pdf/opening-and-closing-of-the-bacterial-rna-polymerase-clamp-24xqot5isk.pdf

Opening and Closing of the Bacterial RNA Polymerase Clamp

New target for inhibition of bacterial RNA polymerase: ‘switch region’

Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3)

Fidaxomicin is an antibacterial drug in clinical use in treatment of Clostridium difficile diarrhea. The active pharmaceutical ingredient of fidaxomicin, lipiarmycin A3 (Lpm), is a macrocyclic antibiotic with bactericidal activity against Gram-positive bacteria and efflux-deficient strains of Gram-negative bacteria. Lpm functions by inhibiting bacterial RNA polymerase (RNAP). Lpm exhibits no cross-resistance with the classic RNAP inhibitor rifampin (Rif) and inhibits transcription initiation at an earlier step than Rif, suggesting that the binding site and mechanism of Lpm differ from those of Rif. Efforts spanning a decade to obtain a crystal structure of RNAP in complex with Lpm have been unsuccessful. Here, we report a cryo-EM structure of Mycobacterium tuberculosis RNAP holoenzyme in complex with Lpm at 3.5 A resolution. The structure shows that Lpm binds at the base of the RNAP "clamp," interacting with the RNAP switch region and the RNAP RNA exit channel. The binding site on RNAP for Lpm does not overlap the binding sites for other RNAP inhibitors, accounting for the absence of cross-resistance of Lpm with other RNAP inhibitors. The structure exhibits an open conformation of the RNAP clamp, with the RNAP clamp swung outward by ~17 degrees relative to its position in catalytically competent RNAP-promoter transcription initiation complexes, suggesting that Lpm traps an open-clamp conformational state. Single-molecule fluorescence resonance energy transfer experiments confirm that Lpm traps an open-clamp conformational state and define effects of Lpm on clamp opening and closing dynamics. We propose that Lpm inhibits transcription initiation by trapping an open-clamp conformational state, thereby preventing simultaneous engagement of transcription initiation factor σ regions 2 and 4 with promoter -10 and -35 elements. The results provide information essential to understanding the mode of action of Lpm, account for structure-activity relationships of known Lpm analogs, and suggest modifications to Lpm that could yield new, improved Lpm analogs.

https://www.biorxiv.org/content/biorxiv/early/2017/12/20/237123.full.pdf

Structural basis of transcription inhibition by fidaxomicin (lipiarmycin A3)

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New target for inhibition of bacterial RNA polymerase: ‘switch region’

Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3)

Structural basis of transcription inhibition by fidaxomicin (lipiarmycin A3)