Rise of The Super-Resistant Bugs − Advances in Therapeutics for Drug Resistant Bacteria
Subhamoy Das*, SantanuMaity and Niren Murthy
Department of Bioengineering, University of California at Berkeley, USA
Submission:April 24, 2018; Published: August 29, 2018
*Corresponding author: Subhamoy Das, Department of Bioengineering,University of California, Berkeley, Hearst Memorial Building, Room 140, Berkeley, 94720, CA, USA, Tel:(512)965-5669 ; Email: subhamoy@berkeley.edu
How to cite this article: Subhamoy Das, Santanu Maity, Niren Murthy. Rise of The Super-Resistant Bugs − Advances in Therapeutics for Drug Resistant Bacteria. Adv Biotech & Micro. 2018; 10(4): 555791. DOI:10.19080/AIBM.2018.10.555791
Abstract
Points to be included:
a) Antibiotics have been used for centuries now – among the first discoveries in medicine.
b) Over usage and non-regulation of antibiotics in developing nations – primary reason for resistance
c) Drug resistance is a real problem
d) Most antibiotics in pre-clinical development are for gram positive, because it was easier target than gram negative bacteria
e) Most drug resistance in gram negatives without any cures
f) New antibiotics are newer versions of the old antibiotics. Paucity of new antibiotics
g) Here we discuss the recent advances in the field, in the past 10 years and where it is headed
Keywords:Multi-drug resistant bacteria; Antibiotics; MRSA; Anti-microbials; VRE; ESKAPE; Therapeutics
Abbrevations:MRSA: Methicillin Resistant Staphylococcus Aureus; VRE: Vancomycin Resistant Enterococcus; ESKAPE: Enterobacteria, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterococcus; GNB: Gram Negative Bacteria; GPB: Gram Positive Bacteria; ESBL: Extended Spectrum Beta Lactamases; MIC: Minimum Inhibitory Concentration; MDR: Multi Drug Resistant
Introduction
Earliest reference about antibiotics in text
Edward Jenner – Penicillin
We have come a long way in the past century. The future is going to be difficult and challenging.Infections caused by drug-resistant gram-negative bacteria (GNB) are a major health problem and have the potential to cause a global health crisis if new antibiotics are not developed. Developing new antibiotics against GNBs has been challenging because of their large repertoire of drug-resistance mechanisms and their low membrane permeability. No new classes of antibiotics have been clinically approved in the last 25 years, which is problematic, because resistance to all existing GNB antibiotics will likely occur within the next 10-20 years, creating the possibility of a post-antibiotic era. There is, therefore, a great need for the development of new pharmacophores that can act as scaffolds upon which new GNB antibiotics can be developed.
Antibiotics are losing efficacy at an alarming rate, due to the rapid spread of drug-resistant bacteria and the slow rate at which new antibiotics are being developed. In the United States alone, at least 2 million people per year become infected with drug-resistant bacterial pathogens[1], and this number is much higher in developing nations such as China, Russia, Brazil, and India[2-4]. Drug-resistant GNBs have the potential to cause a public health care crisis if immediate action is not taken. In 2013, the CDC, NIH, and WHO issued a report, on “Antibiotic resistance threats in the United States, 2013”, in which they grouped bacterial pathogens according to “urgent”, “serious”,and “concerning” threats[1, 5-7]. The “urgent threat” pathogens included many drug-resistant GNB such as Carbapenem-resistant Enterobacteriaceae (CRE), which include E. coli and Klebsiella pneumoniae. In addition, outof the “serious threats” pathogens, 7 of the 12 species belonged to GNB. The most important of these are theextended spectrum β-lactamase producing Enterobacteriaceae as well as the glucose non-fermenting healthcare-associated pathogens P. aeruginosa and A. baumannii [1]. Additionally, the CDC has highlighted “Four Core Actionsto Prevent Antibiotic Resistance”, with one action being the need for alternative drug development. New drugs or new approaches to treating GNB infections are therefore urgently needed.
A key challenge limiting the development of new drugs against GNBs is their low membrane permeability. GNBs have two membranes; an outer membrane (OM) and a cytoplasmic membrane (CM) through which drugs must penetrate, and these two membranes prevent both hydrophilic and hydrophobic molecules from diffusing through GNBs. The two membranes of the GNBs impose severe constraints on the types of molecules that can be pursued as future drugs. Thus, numerous antibiotics have been developed that are active against gram-positive bacteria yet have no efficacy against gram-negative bacteria because of membrane-transport limitations, leading to a great need for effective small molecule scaffolds that can easily permeate GNB.
The treatment of bacterial infections is a central challenge in medicine. For example, in the United States, in 2010, bacterial infections killed more people than AIDs, breast cancer and prostate cancer combined.1 Moreover, antibiotic resistance is a growing public health concern and there is an urgent need for effective treatments for drug resistant gram negative infections. According to Centers for Disease Control and Prevention (CDC), at least 2 million people in the US suffer from infection by drug resistant micro-organisms (bacteria and fungus combined), and 23,000 people die from it. Colistin is an effective antibiotic within the polymyxin family, and it is consideredto be the “last resort drug” for drug resistant gram negative bacterial infections. For example, colistin is effective against infections caused by multidrugresistant Pseudomonas aeruginosa, Klebsiella pneumonia, and many othergram-negative bacteria. However, colistin causes severe nephrotoxicity (kidney toxicity), which limits its clinical use.
Emergence of drug resistant bacteria
Antibiotic resistance is not new, has been happening since the time antibiotics were discovered Horizontal gene transfer–multi drug resistant bacteria. Over use and absence of regulation of broad spectrum antibiotics expedited evolution of the bacterial species(Figure 1 & 2).
Common antibiotic targets
I. Cell wall biosynthesis
II. Cell membrane
III. DNA replication
IV. Protein synthesis
V. RNA synthesis
VI. Folate synthesis / Metabolic
VII. Limitations
VIII. New developments
IX. Potential new targets
Acknowledgments
The authors would like to thank NIH for funding support via R21 AI119115-01, R01EB02000801A1, R01AI117064 grants.
Conflict of Interest
The authors declare no conflicts of interest.
References
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