Bacteria that have evolved resistance to ß-lactam antibiotics can be rendered susceptible once again if the drugs are combined with newly identified small molecule adjuvants called tarocins. Researchers at the pharmaceutical company Merck announced their discovery in a Science paper today (March 9), showing that a cocktail of ß-lactam antibiotic and tarocin could successfully treat mice infected with a normally resistant strain of Staphylococcus aureus.

The authors found “an interesting way to resensitize resistant bacteria to agents that are absolutely fantastic when they work,” said medicinal chemistAmy Anderson of the University of Connecticut who was not involved in the research. “ß-lactams are . . . the go-to antibiotics and being able to get that sensitivity back is absolutely critical.”

ß-lactam antibiotics, which include penicillins such as methicillin, kill bacteria by targeting enzymes that are necessary for producing peptidoglycan—the major component of the bugs’ cell walls. But some species of bacteria—for example, methicillin-resistant S. aureus and S. epidermidis (MRSA and MRSE)—have acquired resistant forms of these enzymes allowing the bugs to proliferate unhindered by the drugs.

MRSA and MRSE are both major causes of difficult-to-treat infections, particularly in hospitals, with MRSA being the second most common cause of death from drug-resistant bacteria. Indeed, the US Centers for Disease Control and Prevention has categorized MRSA as a serious threat.

Recent research has shown that inhibiting the synthesis of teichoic acid—another cell wall component—can restore ß-lactam sensitivity to drug-resistant S. aureus. However, inhibitors of the teichoic acid pathway identified to date “either have eukaryotic toxicity or lack potency,” said microbiologist and immunologistSuzanne Walker of Harvard Medical School who also was not involved in the project.

Merck’s Terry Roemer and colleagues therefore carried out a screen of 2.8 million small molecules to try to find safe and effective techoic acid inhibitors. The researchers found two structurally unrelated molecules, which inhibit an enzyme responsible for the first step in teichoic acid synthesis, TarO, naming the compounds tarocin A and B.

The team showed that combining either of the molecules with a ß-lactam antibiotic could suppress growth of both MRSA and MRSE in vitro, and that neither of the compounds were toxic to human cells. The team then created an improved derivative of the more potent of the two molecules, tarocin A, and showed that it could restore ß-lactam susceptibility to 82 percent of MRSA samples and 77 percent of MRSE samples isolated from patients. They also showed that mice infected with MRSA could be effectively treated with a combination of ß-lactam and tarocin A with no apparent adverse effects. Treatment with either the antibiotic or tarocin A alone, on the other hand, failed to clear the infections.

That the tarocins lack activity when used alone was not by chance, but design, Roemer explained. The team chose to focus their efforts targeting a noncritical part of the teichoic acid pathway. Such an approach is unusual, said Anderson, explaining that normally “everybody is looking to kill the bacteria.” But, Roemer said, it has its advantages. For one, “it turns out that clinical trials [are] much more straightforward if the adjuvant is nonbioactive,” he said. Compared with an entirely new antibiotic that itself kills bugs, the regulatory path to clinical development of an inactive adjuvant is “faster, easier and less costly,” Roemer added.

Another benefit of targeting nonessential pathways, Roemer noted, is that it provides scientists with options. “It opens up more targets and new chemical space to consider,” he told The Scientist. “You just have to pair it with an existing antibiotic.”

S. H. Lee et al., “TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci,” Science Translational Medicine,8:329ra32, 2016.

In a similar vein to the above, beta-lactamase inhibitors are drugs that are combined with a beta-lactam antibacterial drug to protect the beta-lactam from destruction by beta-lactamase enzymes produced by resistant bacteria. Some current product employing this strategy are amoxicillin+clavulanic acid, pipericillin+tazobactam, ampicillin+sulbactam, and ceftazidime+avibactam.

I am agree with all of you.

I think with all of these we have to manage infectious organism in hospital setting and use the proper antimicrobial policy.

This is ever becoming a challenge. I also agree with all of you. Resistance to antimicrobials in our set up is assumed to be worrying yet no publication exists to back it up. My group has been prompted to carry out the research on rationalization of antibiotics use, and I hope to share the findings with you.

These are some of the strategies can be employed in future

a) Delivery of a rationally designed CRISPR-Cas system that resensitizes the drug resistant bacteria and proportionately increase the number of sensitized bacteria population, which can be killed by the approved and useful antibiotics (Yosef et al., 2015; PNAS).

b) Sophoroliplid (type of green biosurfactant) washings @ 20 g/L at 50° C with 35 kHz of ultrasonication for 15 min were effective in removing residual antibiotics, ARGs and ARBs from the contaminated soil and also they demonstrated that whether these treated soil can be suitable for agriculture production by growing lettuce on it (Ye et al., 2015, Ecotoxicology and Environmental Safety)

c) Rationalised use, Educate the Clinicians (Human and vets), people and politicians regarding the impact of ARBs. 

In my opinion antibiotics along with probiotis may be going to solve the problem or we have to see some alternate to antibiotics.

Alternative antimicrobial with a combination of compounds that work synergistic ally is the best option. 

I would say trying to make the host being stronger making them able to deal with infecting organism by itself with out the need of killing agents. If we can do this in population the burden of development of resistance should decrees in a period of couple of decades. Possibly eliminating the whole infecting agents  itself. 

To my understanding and experience, the best strategies include:

1. Appropriate use of antimicrobial(especially considering dose, duration, drug interaction, spectrum)

2. Continued discovery of new antimicrobial

3.Controlling and managing veterinary use and inevitable human exposure to antimicrobial

4. Using only limited numbers of antimicrobials as prophylaxis

5. Preparing appropriate, evidence based and  updated guidelines on antimicrobial use

6. Updating the antimicrobial resistance patterns on different areas to the health professionals

7. Devising the controlling/restricting the prescribing and dispensing of antimicrobial according to the levels of the health settings, experts and facilities.

I hope that following paper be useful.

Best regards

Article Strategies to Combat Antimicrobial Resistance

I  think medicinal plants could help.

I invite you to read my paper:

I welcome your feed back .

Regards 

Emad

This is he World Health Organization's Global Action Plan against antimicrobial resistance:

http://www.who.int/drugresistance/global_action_plan/en/

The pharmacists need to discover new antimicrobials and many corporate bodies should support in their clinical trials and subsequently in the production of those with successful outcomes. Right now, the pharmacists are not getting the financial support as it was many years back. Once there are many therapeutic options to various infections, the issue of antimicrobial resistance will begin to decline, then every other measures can be applied.

Elimination of resistant and development of body strength is the  best way to control with teach of general hygrne maintainance should serve the purpose I can say.

At present, there is paucity of information regarding usage of antibiotics & their resistance in the hospital.  Check  NCDC website for recent updates.

GMO is universally killing microbes.   Legumes have suffering microbiomes for nitrogen fixation and nodes in the soil are half the size.   It is estimated we have only 40% of the microbiome diversity.   I think any strategy should address all of the things that are universally harming  microbiomes: pesticides,  antifungals, antibiotics in animal feed, etc., need to be stopped and regulated.  Antibiotic resistance is affected by so much happening outside of health interests.

Humanity's antimicrobial resistance crisis is like a man, full of bravado, wearing bright clothes and shouting insults loudly, entering a field of containing many bulls who are fighting with each other. Of course, he will draw attention and will soon become the focus of the bull's collective and antagonistic attention.

Antimicrobials and resistance to them is only one way in which members of the microbial world contend with each other for food and other resources. Evolutionary processes have conserved old solutions to this conflict and rapidly developed new 'solutions' to new challenges presented by both the environment and humanity. This means that there will be no singl, long term  'golden solution' to the problem of antimicrobial resistance. Rather, we as a species need now to develop a suit of strategies by which humans present as small a profile as possible to the microbial world in the future. In other words, the man entering the field of bulls needs to be as quiet and discreet as possible, and should not use agressive tactics unless absolutely called for.

Carolyn Michael

Prescribing an antimicrobial should have a thoughful evaluation of risk, knowing the landscape of AMR in the region, and the decision in most occasions should be collective.  Doing cultures to evaluate positivity or negativity to supress/alter the antibiotic as soon as possible should be mandatory in the majority of clinical cases. Not doing this is one of the biggest problems in medicine, leading to a cascade of subsequent errors/reactions and new admissions of patients.

Investment in healthcare hygiene and inspection of practices also helps. A lot! Surveys estimated that doctors do not comply with hygiene practices as should be. Nurses do best in that field.

Screening patients at risk of carrying for MDRO is also a good strategy to prevent spread.

It has also been proved by others that diversification of the antimicrobial panels used in health faccilities helps reducing resistance.

As cited the more the microbiome diversity the human has the better, in particular to fight gut pathogens. This is a field in expansion.

In the end bacteria will always accumulate or lose resistance genes, and be selected by antibiotics.

So, prescribing an antibiotic should be the last resort, and not prescribing could be in many cases the better choice.

I invite you to read my paper

https://www.researchgate.net/publication/323968180_Overcoming_problems_of_poor_drug_penetration_into_bacteria_challenges_and_strategies_for_medicinal_chemists

Kind regards

Thank you, dear Davide

https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance